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2018-02+Science增刊-肿瘤免疫治疗在中国

A Sponsored Supplement to Science

Precision medicine and cancer immunology

in China Sponsored by

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PRECISION MEDICINE AND CANCER IMMUNOLOGY IN CHINA

35 From big data to knowledge in precision

medicine

Dechao Bu, Shaoliang Peng, Haitao Luo et al.

38 The role of circulating cell-free DNA in

the management of cancer in China

Ying Hu, Yanhui Chen, Lei Zhang et al.

44 Next-generation sequencing–based

testing for cancer precision medicine in China: A review of technologies and validation procedures

Weifeng Wang, Weiwei Shi, Ming Yao et al.

49 ctDNA-NGS: The key to unlocking a

molecular diagnostic revolution in the heart of Asia

Ying Hou and Kang Ying

52 Adoptive cell transfer therapy: A

strategic rethinking of combination cancer therapy

Minghui Zhang

immunology in China

About the cover: An artist’s depiction of two traditional Chinese dragons surrounding a black pearl, symbolizing how precision medical treatment can overcome tumor cells using genetic research.Cover: ? 2018 Haitao Zhao (PUMCH)Design company: Jzhmed

This supplement was produced by the Science /AAAS Custom Publishing Office and sponsored by BeiGene, Ltd.

Editors: Sean Sanders, Ph.D.; Jackie Oberst, Ph.D.Proofreader/Copyeditor: Bob French Designer: Amy Hardcastle

Materials that appear in this supplement have not been peer-reviewed nor have they been assessed by Science . Articles can be cited using the following format: [AUTHOR NAME(S)] [CHAPTER TITLE] in

Precision medicine and cancer immunology in China. (Science /AAAS, Washington, DC, 2018), p. [xx-xx].

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Director, Global Collaboration and Business Development, Asia xchu@https://www.wendangku.net/doc/d618592110.html,

+86-131-6136-3212

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INTRODUCTIONS 3drug tolerance—is a foundational aspect of the ancient art of

traditional Chinese medicine, practiced for centuries. Today, China’s medical practitioners depend less on ancient remedies and more on evidence-based practice. They bring with them an appreciation for the benefits and rationale of personalizing treatments to each patient. Therefore, to them, the shift from generalized therapies to precision medicine is perhaps an easier and more logical one to make than for those trained in westernized settings.

In order for precision medicine—the term that now appears to have

dislodged “personalized medicine”—to be successful, accurate characteri-zation of the patient is necessary. Various biomarkers provide the nec-essary data, collected through a variety of 'omics techniques including next-generation DNA sequencing (genomics), analysis of protein levels in blood or tissues (proteomics), or determination of RNA levels (transcrip-tomics). However, identifying and characterizing biomarkers that accu-rately reflect a physiological state (normal or diseased), or response to a particular drug or therapy, has turned out to be challenging. Add to this the complication that biomarkers may differ between population groups, or indeed between individuals, and that tracking these biomarkers as the patient’s status changes can be onerous, and the future of precision medicine could be described as bleak.

This pessimistic outlook has not stopped researchers from pushing for-ward in their search for accurate and robust biomarkers. Big data analysis is helping, by providing a means to crunch millions of datapoints to yield associations that are not at first obvious. It is hoped that these associations will point to the presence of predictive biomarkers or potential targets for therapy, and also help to predict the risk of disease, ascertain the proba-bility of positive clinical outcomes, and evaluate therapeutic efficacy. Such biomarkers are also the ultimate goal of many next-generation sequencing studies being performed on a range of samples, including tumor tissue and circulating cell-free DNA. Applications of this technology in the clinic are bringing researchers closer to real-time biomarker tracking, with implications for cancer detection and the development of safe, effective treatments.

New immunotherapy treatment modalities, such as the use of checkpoint inhibitors, cytokines, and chimeric antigen receptors, are being developed at an increasingly rapid pace, and the success of such therapies depends heavily on extensive knowledge of individual patients, for which high-qual-ity biomarkers are especially important.

The articles presented in this booklet cover many of the topics above, with a focus on precision medicine research currently being performed in China. Researchers there are determined to overcome every obstacle to detecting and exploiting genomic and proteomic biomarkers in a clinical setting for the benefit of their patients. They also hope their insights will advance the practice of precision medicine both domestically and worldwide.

Sean Sanders, Ph.D.Jackie Oberst, Ph.D.

Science /AAAS Custom Publishing Office

biomarkers for precision medicine

Applications of this technology in the clinic are bringing researchers closer to real-time biomarker tracking.

antibodies, and combination therapies for cancer treatment. BeiGene also markets ABRAXANE (nanoparticle albumin–bound paclitaxel), REVLIMID (lenalidomide), and VIDAZA (azaciditine) in China under a license from Celgene Corporation.

BeiGene was founded in 2010 based on the premise that the confluence of two major developments—the revolutionary scientific breakthroughs in cancer medicine, and the emergence of the pharmaceutical market in China, where nearly a quarter of the world’s cancer population has limited access to innovative therapies—may allow new biotech leaders to emerge. With Beijing-based R&D, BeiGene recruits from China’s strong scientific talent pool and has developed a drug discovery platform incorporating tumor samples through local hospital collaborations. Its scientific advisory board consists of world-renowned scientists and clinicians and is chaired by Dr. Xiaodong Wang, cofounder of BeiGene, founding director and

architect of China’s National Institute of Biological Sciences, and a member of the Chinese Academy of Sciences and the U.S. National Academy of Sciences.

Over the past seven years, BeiGene has discovered and advanced into clinical development four investigational drug compounds: Bruton’s tyrosine kinase (BTK) inhibitor zanubrutinib (BGB-3111), PD-1 antibody tislelizumab (BGB-A317), PARP inhibitor pamiparib (BGB-290), and RAF dimer inhibitor lifirafenib (BGB-283). Zanubrutinib is in registrational trials both globally and in China, and its global registration program includes a phase 3 head-to-head trial comparing BGB-3111 to ibrutinib, a currently approved BTK inhibitor, with the aim of demonstrating superior depth of response. Tislelizumab is the subject of a strategic collaboration with Celgene and is in registrational trials in China. BeiGene is also testing

tislelizumab in combination with pamiparib and zanubrutinib, respectively. The company plans to initiate additional registrational trials of its assets, both in China and globally, and to advance additional preclinical assets into the clinic.

Building on its scientific roots and research foundation in China, BeiGene has established global clinical development capabilities with a significant presence in the United States, China, and Australia. In addition, the com-pany has domestic manufacturing capabilities, including a multipurpose manufacturing facility in Suzhou and a commercial-scale biologics manu-facturing facility under construction in Guangzhou, established through a joint venture with the Guangzhou Development District. Through its strate-gic collaboration with Celgene, BeiGene also recently acquired Celgene’s commercial operations in China and gained exclusive rights to commer-cialize Celgene’s three approved therapies there, which is expected to help BeiGene prepare for the potential future commercialization of its internally developed compounds and any additional in-licensed compounds in China. BeiGene aspires to be a global biotech leader and is committed to bringing new, potentially life-altering treatments to patients worldwide.Xiaodong Wang, Ph.D.

Founder & Chairman of Scientific Advisory Board, BeiGene John V. Oyler

Founder & CEO, BeiGene

Certain statements found herein may constitute forward-looking statements that involve numerous risks and uncertainties that are described in BeiGene’s filings with the Securities and Exchange Commission, and are made only as of the date of this publication.

A global oncology company rooted in China

T argeted therapy for liver cancer: Challenges and opportunities

Shuzhen Chen1,2?, Jing Fu1,2?,

and Hongyang Wang1,2** L iver cancer is the sixth most prevalent cancer

and the second leading cause of cancer-related death worldwide (1). China alone accounts for over half of the new cases and deaths. It is estimated that in 2015 alone, 466,100 new cases of liver cancer were diagnosed in China and 422,100 deaths oc-curred there (2). Of all the cancers, the survival rate of liver cancer is the poorest—the age-standardized five-year relative survival rate is only 10.1% (3). Due to difficulties in early diagnosis, most liver cancer patients are diagnosed at an advanced stage, losing the opportunity for curative treatments such as liver resection or ablative procedures. Fortunately, the development of innovative tech-nology such as next-generation DNA sequencing has enabled a rapid and dramatic increase in our understanding of the genetic, molecular, and mor-phological changes occurring in individual cancer patients, laying the foundation for the emergence of targeted therapy. Although targeted therapies such as sorafenib treatment have raised hope for advanced liver cancer patients, their clinical benefits remain modest at best (4, 5). It is hoped that target-ed therapy will provide functional and even structur-al corrections at the molecular level, or at least offer a valid alternative to conventional treatment. Howev-er, liver cancer is an extraordinarily heterogeneous disease, which makes it difficult to properly stratify patients for optimal targeted treatment and increas-es the risk of side effects, leading to the persistent failure of targeted therapy (6). In this review, we summarize the progress made in targeted therapy for liver cancer treatment in China and focus on the challenges and opportunities thereof.

Sorafenib

Sorafenib is the first small-molecule targeted drug that has demonstrated a survival benefit in advanced

1International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China

2National Center for Liver Cancer, Shanghai, China

?Joint first author

*Corresponding author: hywangk@https://www.wendangku.net/doc/d618592110.html, hepatocellular carcinoma (HCC) patients (5, 7). It is a multikinase inhibitor of several tyrosine protein kinases, including vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). Sorafenib can also target intra-cellular serine and threonine kinase signaling such as RAF proto-oncogene kinase, including the C-Raf and B-Raf pathways (8–10). Sorafenib was approved as the only standard systemic treatment for HCC mainly on the basis of two studies: the Sorafenib HCC Assessment Randomized Protocol (SHARP) phase 3 trial (conducted in Europe, North America, South America, and Australasia), and a phase 3 ran-domized trial conducted in the Asia-Pacific region. According to these two studies, the sorafenib treat-ment group showed prolonged median survival: 10.7 months in the SHARP study compared to 7.9 months for the placebo group (5), and 6.5 months in the Asia-Pacific study compared to 4.2 months for the placebo (7). However, further analysis of these two trials and results from other studies have shown undesirable tolerability of sorafenib caused by its severe adverse events, including gastroin-testinal, dermatologic, hematologic, cardiovascular, and nervous system side effects (11–16), making patients reluctant to continue the treatment. Drug resistance is another bottleneck issue for sorafenib treatment. Numerous studies have re-vealed significantly differing responses to sorafenib due to tremendous variability in the way HCC progresses (17, 18). Chinese researchers have made serious efforts to decipher the mechanism underly-ing resistance to sorafenib and to identify potential biomarkers predictive of sorafenib response. A study by our team demonstrated that HCC patients with high 26S proteasome non-ATPase regulatory subunit

10 (PSMD10) expression had worse prognosis and

a poor response to sorafeni

b therapy. The overall survival time of sorafenib-treated HCC patients with high levels of PSMD10 was much shorter than those with low PSMD10 (p=0.0099), with the medi-an survival time reduced by more than 40 months (p=0.0099). These results suggest that PSMD10 may be a potential molecular marker in the classifi-cation of HCC patients who may not respond effec-tively to sorafenib (17). In another study, our clinical investigation revealed that HCC patients with low Src-homology 2 domain–containing phosphatase 2 (Shp2) expression benefited from sorafenib admin-istration after surgery. This study showed that Shp2 could promote liver cancer stem cell expansion by augmenting b-catenin signaling and might be a useful indicator when determining chemothera-peuti

c strategies (18).

TARGETED THERAPY FOR LIVER CANCER: CHALLENGES AND OPPORTUNITIES 5

6 PRECISION MEDICINE AND CANCER IMMUNOLOGY IN CHINA

The varied cellular metabolic phenotypes of tumor cells may also affect the efficacy of sorafenib. Inves-tigation of the metabolic characteristics of tumor samples from 63 HCC cases showed huge variation in lipid content and glucose uptake. This study found that the rate-limiting enzyme acetyl-coenzyme A car-boxylase alpha (ACC a) enhanced glucose-derived de novo fatty acid synthesis (FAS) and promoted tu-mor cell survival under energy stress, which contrib-uted to the heterogeneity of metabolic patterns in HCC. Inhibition of ACC a-driven FAS using a specific inhibitor, orlistat, improved the efficacy of sorafenib in xenograft-bearing mice, suggesting that interfer-ing with ACC a-driven FAS could sensitize HCC cells to sorafenib (19). Another study has reported that blocking interleukin-6/signal transducer and activa-tor of transcription 3 (STAT3)–mediated preferential glucose uptake could sensitize liver tumor–initiating cells to sorafenib treatment and enhance its thera-peutic efficacy in vivo (20). These findings suggest that a combination of sorafenib and inhibitors of certain metabolic pathways could be a promising approach for some HCC patients.

EGFR inhibitors

Epidermal growth factor receptor (EGFR) is over-expressed in 40%–70% of human HCCs, a factor that has been proven to be closely linked to the forma-tion and growth of tumors. But EGFR inhibitors have shown disappointing results in clinical trials with un-selected patients (21). A study was conducted in Tai-pei to evaluate the efficacy and safety of vandetanib, an oral inhibitor of both VEGFR and EGFR, in pa-tients with inoperable advanced HCC. The study ob-served no significant difference in the rate of tumor stabilization or vascular change between the vande-tanib group and the placebo group, suggesting that vandetanib had limited clinical activity in HCC (22). Other clinical trials with erlotinib, gefitinib, or cetux-imab showed only limited effects in advanced stage HCC or modest effects at most in phase 2 trials (21).

A better understanding of the mechanisms underly-ing how EGFR signaling influences HCC progression is therefore needed.

A study of the role of EGFR in HCC formation showed that the absence of EGFR in macrophages impaired the development of HCC in mice, where-as mice lacking EGFR in hepatocytes unexpectedly developed more HCCs due to increased compen-satory proliferation after cell damage. Following inflammatory stimulation, EGFR induces interleukin-6 expression in liver macrophages, triggering hepato-cyte proliferation and the development of HCC (23). This study demonstrated that EGFR has different roles in tumor cells than in nontumor cells, provid-ing some explanation of the disappointing results

of anti-EGFR agents in HCC treatment. Other recent research by our team indicates that levels of choline kinase alpha (CHKA) are higher in human HCCs than in nontumor tissues, and that CHKA is associated with tumor aggressiveness and reduced overall survival. Further study has revealed that CHKA could facilitate a functional interaction between EGF and mammali-an target of rapamycin complex 2 (mTORC2), which could contribute to HCC metastasis by promoting AKT (Ser473) activation. In this way, overexpression of CHKA promotes resistance to EGFR-targeted drugs (gefitinib and erlotinib) in HCC, suggesting that dual inhibition of CHKA and mTORC2 could be a way to overcome the resistance of HCC cells to EGFR-targeted therapies (24).

Immunotherapy

GPC3-based immunotherapy

Glypican-3 (GPC3) can be detected in 72% of HCCs, but could not be detected in normal hepato-cytes, cirrhotic liver, or benign liver lesions (25). In addition to being a marker for HCC, GPC3 plays a role in the progression of the disease. It activates Wnt signaling and stimulates cell cycle progression and cell survival (26), indicating that anti-GPC3 therapy could be a therapeutic strategy for HCC treatment. The potential usage of GPC3-derived antibody or peptide vaccines has been explored in HCC immunotherapy (27–29). Disappointingly, in clinical trials these agents showed only limited cura-tive effect (30).

Chimeric antigen receptor T (CAR-T) cells have been heralded as a breakthrough technology due to the substantial benefits observed in patients with relapsed or refractory B-cell malignancies. More than 200 CAR-T cell clinical trials have been initiated so far, most of which are CD-19 specific CARs aimed at treating lymphoma or leukemia (31). Researchers interested in HCC have mainly explored the possibility of redirecting T cells to recognize GPC3 for the treatment of HCC. T cells with CARs

or high-affinity T-cell receptors (TCRs) targeting GPC3 were therefore engineered. Such targeted cells can efficiently recognize and destroy GPC3-positive human HCC cells in vitro and in vivo (32, 33). In a recent study, Li and colleagues developed T cells carrying two complementary CARs—against both GPC3 and asialoglycoprotein receptor 1 (ASGR1)—to reduce the risk of on-target, off-tumor toxicity, while maintaining relatively potent antitumor activity (34). These preclinical studies suggested that

adoptive transfer of GPC3-specific T cells presents a promising therapeutic strategy for treating HCC. Anti-GPC3 CAR-T therapy is now undergoing clinical trials in China.Anti-PD-1/L1Programmed cell death 1 (PD-1) is an immune coinhibitory receptor expressed on immune cells such as T cells, B cells, and natural killer (NK) cells. PD-1 suppresses antigen-specific T-cell activation through interaction with its ligand, PD-L1, which has been observed to be upregulated in tumor cells (35). Clinical trials of antibodies targeting PD-1 or PD-L1 for the treatment of HCC have shown some promising results (36). A recent report in The Lancet evaluated the safety and efficacy of PD-1 inhibi -

tor nivolumab in patients with advanced HCC in an open-label, noncomparative, phase 1/2 dose escalation and expansion trial. The study showed that nivolumab produced durable objective respons-es in long-term survival rates in patients with ad-vanced HCC (37).However, it is important to recognize that in previous studies the response rate to anti-PD-1 as a stand-alone ther-apy was 10%–30% overall, which included immu-nogenic tumors such as malignant melanoma that have a much high-er response rate (36). One possible

explanation for the low response rate might be

the influence of molecules in-volved in immune escape other than PD-1 and PD-L1/2.

Therapy that combines antibodies to block three inhibitory immune checkpoint molecules—PD-1, T cell immunoglobulin and mucin domain 3 (TIM-3), and lymphocyte-activation gene 3 (LAG-3)—has already

been reported to restore the immune response to

tumor antigens of HCC-derived T cells (38). However, there is still a long way to go before such combined antibody therapy can be established and tested in clinical trials.Potential targeted therapies Recent findings have also shed light on other potential targets for HCC treatment. The development of HCC is a multistep process with high intratumoral heterogeneity, including alterations in tumor microenvironment, signaling

pathways, and energy metabolism patterns. In

TARGETED THERAPY FOR LIVER CANCER: CHALLENGES AND OPPORTUNITIES 7

FIGURE 1. Schematic representation of the signaling network and agents involved in targeted therapy

for liver cancer. Erlotinib and gefitinib are tyrosine kinase inhibitors targeting EGFR. The PI3K/AKT/

mTOR/p70S6 and Ras/Raf/MEK/ERK pathways are involved when EGFR signaling is activated, and can be blocked by independent inhibitors. Vandetanib and sorafenib are multikinase inhibitors of several tyrosine protein kinases such as VEGFR and PDGFR. GPC3 increases the binding of Wnt to FZD, which

results in the stimulation of b -catenin transcriptional activity. Approaches to targeting GPC3 in HCC such

as anti-GPC3 antibody or GPC3-targeted chimeric antigen receptor have shown some promise in differ -ent studies. EGFR, epidermal growth factor receptor; PDGFR, platelet-derived growth factor receptor;

GPC3, glypican-3; Ab, antibody; VEGFR, vascular endothelial growth factor receptor; PI3K, phosphati -dylinositol-3 kinase; mTOR, mammalian target of rapamycin; p70S6, ribosomal protein S6 kinase; MEK, MAPK/ERK kinase; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase;

DSH, dishevelled; FZD, frizzled; HIF-1a , hypoxia-inducible factor 1-alpha.

8 PRECISION MEDICINE AND CANCER IMMUNOLOGY IN CHINA

previous reports, it has been noted that adenosine monophosphate (AMP)–activated protein kinase (AMPK) serves as an energy sensor in eukaryotic cells and plays a role in linking metabolism and cancer development (39–41). However, our recent research has demonstrated that activation of AMPK by the first-line medication metformin for the treatment of type 2 diabetes, not only inhibited HCC cell growth in vivo, but also augmented the growth inhibition induced by the chemotherapy drug cisplatin in these cells (42). Another study observed an imbalance of gut microflora as well as intestinal inflammation in chronic treatment of rats with the carcinogen diethylnitrosamine. Modulation of gut microbiota by probiotics dramatically mitigated liver tumor growth and spread in vivo (43). These studies indicate that an intervention strategy based on studies of HCC heterogeneity may present a new avenue for therapeutic intervention to treat the disease.

Perspectives

An improved understanding of the molecular pathways that drive development of HCC has led to the identification of various biomarkers and the evaluation of several agents specifically targeted

to tumor cells with particular molecular features. However, clinical trials undertaken worldwide have documented only occasional positive responses to such treatments. To date, no single agent or single targeted therapy has been formally found to be a cure for HCC in clinical trials. An increasing number of studies have demonstrated that intratumoral heterogeneity in individual patients is a roadblock for HCC targeted therapy. Therefore, the efficacy of targeted therapy requires a thorough understanding of the tumor microenvironment, metabolism,

and gut microbiota of an individual. Meanwhile, combined therapies may be more effective than the administration of a single agent. IL-6 and PD-L1 blockade, or sorafenib combined with anti-PD-L1 monoclonal antibody, have demonstrated better efficacy than a single inhibitor in mouse models (44, 45). It is hoped that the establishment of combined therapies can offer a way to successfully manage HCC patients in the future.

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The challenges of radiation oncology in the era of precision medicine

Ligang Xing and Jinming Yu* R adiotherapy is an essential treatment

in the management of cancer. Seventy percent

of all cancer patients will get radiotherapy as

at least part of their treatment (1). Advances in physics, mathematics, computer science, electrical engineering, and radiobiology have significantly improved the safety, precision, and efficacy of radiotherapy, the concomitant control of tumor growth, and the probability of a cure for many cancer sufferers. In recent years, the sequencing of the human genome has paved the way for precision medicine, which aims to deliver “the right treatment to the right patient at the right time.” Although discoveries arising from studying the genome have affected the delivery of chemotherapy and targeted biological agents (2), they have yet to impact the clinical use of radiotherapy. In this new era of precision medicine, radiotherapy poses both great challenges and great opportunities for physicians and researchers.

Progress in modern radiotherapy techniques New technologies have been the main driving force behind innovations in radiation oncology over the last two decades. Technological advances have been put to clinical use, leading

to better localization of the radiation dose and less damage to healthy tissue. These methods include technologies such as three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), 3D brachytherapy, stereotactic radiotherapy, image-guided and adaptive radiotherapy (IGRT and ART), and charged particle radiotherapy using protons and carbon ions. Using 3D-CRT and IMRT, we can make the radiation conform to the shape of the target volume, solving the problem of irradiating complex targets that lie close to critical healthy structures. 3D-CRT and IMRT are routinely and

Department of Radiation Oncology and Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital Affiliated with Shandong University, Shandong Academy of Medical Science, Shandong, China

* Corresponding author: sdyujinming@https://www.wendangku.net/doc/d618592110.html, successfully applied for head and neck cancers, prostate cancer, and many other common cancers including those of the lung, liver, esophagus, and breast (3, 4). In the past 10 years, there has been rapid growth in clinical research on and application of stereotactic ablative body radiotherapy (SABR), also known as stereotactic body radiation therapy (SBRT), for cancers such as lung, liver, spine, pancreas, and prostate. For example, by accurately delivering high-dose radiation to the tumor, SBRT has emerged as the standard of care for medically inoperable stage I non–small cell lung cancer (NSCLC) and may even outperform surgery in operable patients (5, 6).

Genomics for personalized radiotherapy

From 3D-CRT and IMRT to SBRT, two factors limit the efficacy of radiotherapy: (1) defining the target, or differentiating between tumor and normal tissue; and (2) determining the appropriate total dose of radiation and its “fractions”—the number

of separate treatments into which the total dose is divided. In clinical practice, radiotherapy dosages and fractions have been determined empirically, which has resulted in reasonable disease control and acceptable levels of toxicity. However, results suggest that current radiotherapy dosing protocols can be further optimized with a modern precision oncology approach, such as gene profiling to detect relevant biomarkers or biomarker signatures that would inform clinicians of a particular patient’s sensitivity or resistance to radiotherapy. Existing tests that predict a patient’s sensitivity to radiation can be grouped into three categories: those

that determine intrinsic radiosensitivity, those

that determine tumor oxygen levels, and those that determine a tumor’s chance of growing (7). Unfortunately, none of these approaches is practical for clinical application. Radiotherapy is used in different settings depending on the site

of the disease, so the clinical utility of a molecular biomarker signature indicating sensitivity to radiation would vary depending on the clinical application. The development of clinically relevant radiosensitivity molecular signatures is therefore challenging (8).

Recently, Scott and colleagues identified 10 genes that could index radiosensitivity (9). This could allow the radiation dose to be individually tuned to a tumor’s radiosensitivity and provide

a framework for designing genomically guided clinical trials in radiation oncology. Being able to increase radiation dosage for more resistant tumors and lower it for more sensitive tumors would also

THE CHALLENGES OF RADIATION ONCOLOGY IN THE ERA OF PRECISION MEDICINE 9

10 PRECISION MEDICINE AND CANCER IMMUNOLOGY IN CHINA

lower the risk of complications from the therapy.

It should be emphasized that tumor genomic data gives information only about a tumor’s intrinsic radiosensitivity. Additional biological insights about the tumor and its microenvironment, as well as information about the patient, are also important for optimizing radiotherapy dosing.

Combining radiotherapy with targeted therapy Biomarkers that can predict tumor sensitivity to therapy are considered the gatekeepers necessary to develop precise and personalized medicine (10). These biomarkers are therapy-specific, and can therefore aid in therapeutic decision-making. For example, mutations in the epidermal growth factor receptor (EGFR) gene have been shown to predict the benefit derived from using tyrosine kinase inhibitors (TKIs), while anaplastic lymphoma kinase (ALK) gene rearrangements have been shown to predict the efficacy of ALK inhibitors in treating NSCLC (11, 12). Building on the preclinical rationale that inhibitors of EGFR function create a strong sensitivity to radiation (13), serial clinical trials have been conducted to test combinatorial treatments using EGFR inhibitors plus radiotherapy. In one pivotal phase 3 trial, adding the chemotherapy drug cetuximab to radiation improved localization of therapy in locally advanced head and neck squamous cell cancer and improved overall survival (14). However, phase 3 trials that evaluated cetuximab in combination with chemoradiotherapy for NSCLC and esophageal cancer all failed to improve overall survival in an unselected patient population (15, 16).

Phase 1 and 2 trials of EGFR TKIs in combination with radiotherapy for locally advanced NSCLC or metastatic NSCLC have shown a favorable safety profile and some encouraging outcomes (17, 18). However, these trials were all performed in pa-tients without information on whether their tumors carry the EGFR mutation, making the results less informative. These studies highlight the need for predictive biomarkers in cases where targeted therapy is combined with radiotherapy.

Radiotherapy combined with modern

immune-targeted therapy Understanding of the interaction between the immune system and tumor growth has led to the development of modern cancer immunotherapies. These include cancer vaccines, chimeric antigen receptor T-cell (CAR-T) therapy (in which immune system T cells are reengineered to act against

a cancer), and immune checkpoint inhibitors, which interfere with proteins that prevent T cells from responding to cancer. Immune checkpoint inhibitors targeting several types of proteins, including cytotoxic T-lymphocyte antigen-4, programmed death-1 (PD-1), or programmed death ligand-1 (PD-L1), have demonstrated clinical efficacy against a broad spectrum of tumor types—a significant step for both science and medicine (19). Early studies revealed that radiotherapy could provoke an immune response not only at the irradiated site, but also at remote, nonirradiated tumor locations—the so-called “abscopal effect.” Cell death in the irradiated tumor can enhance antitumor immunity by inducing the expression of certain antigens on tumor cells and by activating lymphocytes to attack the tumor. Preclinical and clinical studies have demonstrated the efficacy and safety of radiotherapy combined with immunotherapy (20, 21). Currently, clinical trials of such combined treatments for a variety of tumor types are underway.

Most modern immunotherapies are not yet cost-effective, especially for patients in China, and immune checkpoint inhibitor therapy is not sufficiently precise yet. A crucial step in refining these therapies is the identification of biomarkers that can predict a tumor’s response to checkpoint blockades (22). The overexpression of the PD-L1 antigen, the presence of tumor-infiltrating immune cells, or a variety of molecules in the tumor’s microenvironment may be important predictive biomarkers and are being extensively explored. However, they are not yet sufficiently predictive to allow them to be used to routinely stratify patients. Gene analysis is a new approach for judging the potential clinical benefit of checkpoint inhibitors (23), but further preclinical and clinical studies are necessary before it can be applied in clinical practice. In order to move the strategy successfully into the clinic, it is also critical to clarify the appropriate fractions and doses of radiotherapy and the suitable combinations of radiotherapy and immunotherapy (24).

Molecular image-guided precision radiotherapy Imaging plays a critical role in precision medi-cine, from screening and early diagnosis to guiding treatment, evaluating responses to therapy, and assessing the likelihood of disease recurrence (25). Rapid advances in imaging technologies permit better anatomical resolution and provide noninva-sive measurements of functional and physiological properties of tissues and lesions at the molecular

level. The development and application of molec-ular imaging techniques brings new opportunities for creating more precise treatment.

Novel molecular imaging approaches are being developed and validated in many critical molecular pathways, such as glucose and amino acid metabolism, cell proliferation, hypoxia, angiogenesis, and receptor expression. The concept of “biological target volume” has been introduced as a factor when determining the intensity of radiotherapy needed for treatment (26). We are looking for the best way to use molecular imaging to guide radiotherapy for certain cancers, either to help define the target volume to be irradiated, or to aid in patient stratification. It was recently reported that an escalated radiation dose to treat a particular type of lung tumor detected by a mid-treatment positron emission tomography (PET) scan allowed clinicians to deliver higher-dose radiation to the more aggressive areas of the tumor and improve local control of tumor growth without increasing radiotherapy-induced lung toxicity (27). PET and computed tomography scans could also identify and delineate hypoxic areas that could be targeted for elevated dosing in lung cancer patients (28).

The role of cancer imaging in precision medicine is being explored from another angle as “radiomics,” which assesses a large number of imaging features that characterize the observable properties of a tumor, using descriptors beyond simply its size to predict clinical outcomes with increased prognostic power, or even correlate with gene expression profiles (29). This approach could be important in helping to stratify patients who are at risk of disease recurrence (30, 31).

In summary, precise radiation therapy is being explored at four different levels: (1) clinical features such as the molecular structure of the tissue, cancer stage, and tumor volume and location(s); (2) adaptive radiotherapy based

on images collected during treatment; (3) biomarker-guided therapy; and (4) personalized radiotherapy delivery schedule (32). We believe that with multidisciplinary guidance, the strong support of science and technology, and an eye

to cost-effectiveness, precision radiotherapy that incorporates radiobiology, bioinformatics, and molecular imaging will eventually be realized.

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32. J. Y. Jin, F. M. Kong, Adv. Exp. Med. Biol.890, 175–202 (2016).

Acknowledgments

This review was supported by grants from the National Health and Family Planning Commission of China (201402011), the National Key Research and Development Project of China (2016YFC0904700), the National Natural Science Foundation of China (81572970), and the Innovation Project of the Shandong Academy of Medical Science.

THE CHALLENGES OF RADIATION ONCOLOGY IN THE ERA OF PRECISION MEDICINE 11

PRECISION MEDICINE AND CANCER IMMUNOLOGY IN CHINA

notherapy include chimeric antigen receptor (CAR) T-cell therapy, immune checkpoint inhibitors, and cancer vaccines. These treatments have demonstra-ble clinical benefits and show great promise. How -ever, there are still some challenges that precision medicine and immuno-oncology must confront.For precision medicine the most pressing are:

1. T umor heterogeneity and molecular evolution Tumors exhibit tremendous genetic heterogene-ity, both among different kinds of tumors and within a single tumor. This creates phenotypic variation,

posing a significant challenge to personalized cancer medicine. Intratumor heterogeneity increases the complexity of cancer prognosis and likely contrib-utes to tumor metastasis under therapeutic pressure. Exploring genomic alterations by time series analysis can identify the factors that drive a tumor’s evolution during treatment, which may identify the molecular targets of resistance or tumor progression. Rapid advances in technology for studying tumor heteroge-neity would help us understand the tumor genomic landscape. Among such technologies are liquid bi-opsy assays of circulating tumor DNA, detection and analysis of circulating cancer stem cells, and multire-gion next-generation sequencing.

2. Drug resistance

Understanding the clonal make-up of tumors, their molecular evolution, and their response and resis-tance to drugs poses perhaps the greatest challenge, not only to the application of traditional therapies, but also to personalized cancer medicine. To improve an individual’s treatment response and clinical out-comes, clinicians are obliged to inspect the evolving nature of the cancer genome. Moreover, combina-tional cancer treatments that target complementary signaling pathways, or harness the immune system through immunotherapy, have promise to overcome resistance while improving efficacy.

3. Shortage of agents that target specific genomic aberrations

Precise targeted therapy, which is based on the genomic characteristics of an individual patient and the mutations identified in their particular cancer, is limited by a shortage of biochemical agents that target specific genomic aberrations. In clinical prac -tice, it is common to detect significant gene muta -tions in a cancer patient but to have no existing drug that can target those mutations. Or, as also happens, the targeted agent used has little antitumor efficacy. This may be a result of tumor heterogeneity (in which clones of resistant tumor cells survive and proliferate)

Jianzhen Lin 1, Anqiang Wang 2,

Junyu Long 1, Haohai Zhang 1, Yi Bai 1, Xiaobo Y ang 1, Jie Pan 3, Ke Hu 4, Lin Zhao 5,

Xinting Sang 1, and Haitao Zhao 1,6*

ancer is a group of highly heterogeneous dis-eases in which dysregulation of key cellular processes leads to neoplastic transformation. Tumor immunity and suppression of the immune response within the tumor microenvironment support its progression. In the past few years, dramatic advances in DNA se-quencing technologies have facilitated key insights into the genomic alterations and somatic mutations that enable cancer formation and progression, allow-ing for significant advances in precision medicine. The broad lexicon of precision medicine describes the narrowing of medical care to the characteristics of an individual patient. It improves upon the current approach of stratifying patients into treatment groups based only on phenotypic biomarkers, and instead makes use of a patient’s molecular information (in-cluding genomics and proteomics) to inform diagno-sis, prognosis, treatment, and disease prevention for that individual.

Oncology is at the frontline of precision medicine. It is evolving from the previous model of administer-ing cancer therapeutics through a unified treatment regimen based on cursory tumor classification, to one that applies the precise molecular profile of an individual’s cancer genome to optimize personalized treatment. Another new and highly successful thera-peutic approach to cancer, immunotherapy (Science ’s 2013 Breakthrough of the Year), has created great excitement for clinicians, patients, researchers, and scientific journals. Current strategies in cancer immu -1

Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (PUMC), Beijing, China 2

Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute, Beijing, China 3

Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and PUMC, Beijing, China 4

Center of Radiotherapy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and PUMC, Beijing, China 5

Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and PUMC, Beijing, China 6

Center of Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and PUMC, Beijing, China *

Corresponding author: zhaoht@https://www.wendangku.net/doc/d618592110.html,

The role of multidisciplinary efforts in precision medicine and immunology for clinical oncology

and the variability in the drug’s effect on the targeted genes, or the presence of nonidentical molecular pathways in different patients due to inherent physio-logical and biochemical differences.

For cancer immunotherapy treatments, the most pressing challenges are:

https://www.wendangku.net/doc/d618592110.html,ck of a definitive response to treatment

In many immunotherapy trials, durable responses and extended, long-term survival are seen only in a subset of patients, and it has been reported in some clinical cases that immunotherapy treatment could even promote cancer progression. These challenges highlight the importance of identifying distinguishing clinical and molecular characteristics that can ex-plain the differential response. Clues to what factors might predict a patient’s response to therapy must be sought, and clinicians must be cognizant of overpre-scription in refractory patients.

2.Identification of suitable patients

The limitations of immunotherapy approaches have aroused researchers’ attention. CAR-T therapy, for example, has had clinical success against lymphocytic malignancies, but not against more common solid tumors. Even though antibodies that modify immune function can help patients defend against tumors, overall response, rates are still relatively low, ranging from 10% to 30%. Thus, precisely identifying which patients are likely to benefit from immunotherapy

is an important issue to address. Identifying unique clinical, genomic, and molecular patient character-istics will help researchers identify those factors that might predict response, and presents an opportunity to heighten response in refractory patients. Biomark-ers are crucial to identifying suitable patients, but the complexity of the immune system makes their devel-opment a challenge.

3.Improving efficacy using combinational therapies There is considerable current interest in combining treatment modalities to improve the effectiveness

of immunotherapies in a broad array of patients. This includes immunotherapies used in conjunction with chemotherapy, radiotherapy, targeted thera-py, and even other immunotherapies. But caution

is recommended. Our understanding of biological mechanisms leads us to expect additive or synergistic responses from such combined treatments. However, the complexity of the immune response could lead to unexpected, even serious, adverse events. Crucial-ly, immunomodulatory therapies carry distinct risks, including autoimmune reactions that can be fatal if doctors are not alert and ready with proper treatment.

To overcome these tough challenges, precision medicine and immunology for clinical oncology require multidisciplinary efforts. Large-scale genomic data needs to be integrated with clinical data, analyzed, and translated into information that can guide clinical decisions. Multidisciplinary efforts can also ensure the rational application of cancer immunotherapy and combinational therapies by using multi-omics data to improve the diagnosis, prognosis, and treatment of cancer.

The Department of Liver Surgery and the Center for Translational Medicine at Peking Union Medical College Hospital have been focused for several years on researching precision tumor medicine and im-munotherapy and their translation to clinical use. As personalized cancer medicine moves to the clinic, conceiving of cancer as a systemic, highly heteroge-neous and complex disease becomes even more apt. Quality cancer care demands that we form a multidis-ciplinary team (MDT) of highly qualified health care professionals, with medical oncologists at its core. We see the characteristics of our MDT as including:

1. A multidisciplinary approach

Our MDT members come from specialties includ-ing hepatobiliary surgery, radiology, radiotherapy, medical oncology, and pathology. Also on the team are experts in cancer biology and bioinformatics who can help interpret information on genomic aberra-tions. We strive to translate dispersed knowledge into an integrated, coherent, and personalized treatment regimen.

2.A patient-centric model

Patients’ perceptions of their care are created by the quality of the care, the outcome of the treatment, the empathy displayed by the physician and health care team during their interactions, and each patient’s individual world view. Therefore, the consulting mod-el of our MDT practice is patient-centric. This means that all decisions consider the relationship between the patient, his or her family, and our health care team. We provide face-to-face counseling for every patient, and guarantee no less than a half-hour con-sultation for deciding on a personalized therapeutic regimen and answering patient questions.

3.Guideline-first decision making

A core principle of our MDT decision-making is “guideline-first,” which means that every decision

is evidence-based, and that each patient is treated according to clinically accepted and approved guide-lines. The goal is to provide appropriate therapy for cancer patients to prolong their overall survival.

THE ROLE OF MULTIDISCIPLINARY EFFORTS IN PRECISION MEDICINE 13

PRECISION MEDICINE AND CANCER IMMUNOLOGY IN CHINA

Current status of immunotherapy in advanced HCC

Shukui Qin *

rimary liver cancer, consisting mainly of hepa-tocellular carcinoma (HCC), is one of the most com-mon cancers worldwide, with especially high prev-alence in China and a growing incidence: 782,000 new cases were reported worldwide in 2012 (1, 2). As one of the leading causes of cancer-related deaths, HCC was responsible for an estimated

746,000 deaths worldwide in 2012 (2). China alone accounted for more than 50% of both new HCC cases and HCC-related deaths globally (3). Chronic infection due to hepatitis B virus (HBV) or hepatitis C virus (HCV) contributes to an estimated 75% of all HCC cases (4). In the Asia-Pacific region, more than 75% of cases are associated with HBV infection (5). Surgical resection or orthotopic liver transplant (OLT) offer the best chance for successful treatment of HCC (6). However, surgical resection, liver trans-plantation, and radiofrequency ablation (RFA) are only applicable to a small portion of patients with well-preserved liver function who have early-stage or localized HCC (7). Due to difficulties in early diag -nosis, most HCC cases are locally advanced or show distant metastases at the time of diagnosis. These patients generally have a poor prognosis, with me-dian survival of 6 to 20 months (8), and a five-year survival rate of less than 16% (9).

For local advanced or metastatic HCC, systemic therapy is often used as an important palliative treat-ment. Various conventional systemic chemotherapy regimens such as doxorubicin have been used clini-cally, although there are few well-controlled studies demonstrating the efficacy of systemic chemother -apy in the management of HCC (10). In 2012, our group was the first to demonstrate that a regimen of “FOLFOX4” (oxaliplatin, 5-fluorouracil, and leucov -orin) significantly improved the objective response rate (ORR) and prolonged overall survival (OS)

compared with doxorubicin alone in a randomized phase 3 clinical trial in Chinese HCC patients (EACH

People’s Liberation Army Cancer Center of Bayi Hospital affiliated with Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China *

Corresponding author: qinsk@https://www.wendangku.net/doc/d618592110.html,

4. A personalized therapeutic regimen

Personalizing cancer care implies using MDTs for clinical decision-making, since personalized care requires input from a range of different scientific and care domains. In our teams, clinical information and genomic profiling results are reviewed by profession -als to identify clinically significant results. Patients for whom traditional therapies such as surgery, chemo-therapy, or radiotherapy have failed, or who have elected to give up such treatments to try targeted therapy, are matched with a targeted therapy or immunotherapy regimen if one is available. These treatments might be administered through a clinical trial or using a drug approved by the China Food and Drug Administration or the U.S. Food and Drug Administration. The team also creates personalized therapeutic regimens using cancer immunotherapy or combinational therapy based on individual clinical characteristics, genomic aberrations, and the specific microenvironment of each tumor.

5. Public welfare

The operation of our MDTs is supported by the Chinese Precision Medicine and Immunotherapy for Clinical Oncology Fund, which is a public welfare organization affiliated with the China Social Welfare Foundation. We primarily provide free services to hepatobiliary cancer patients, including multidisci-plinary consultation, tumor genomic sequencing, and protein expression analysis to identify immune system biomarkers. Our mission is firstly to raise awareness of both current achievements using targeted thera-pies and immunotherapy, and of the potential and limitations of these therapies; and secondly to guide patients in seeking out clinical trials where their tu-mors can be better profiled and they can gain access to novel treatments. We also plan to develop more clinical trials to implement personalized therapeutic regimens.

Despite some obvious challenges, the largely en-couraging clinical results from targeted therapeutics and biomarker-guided clinical trials are fueling fur-ther technological advancements in next-generation sequencing technology, data interpretation, and the associated preclinical and clinical cycles of drug de-velopment. All of this translates into a major shift in clinical practice. Moreover, cancer immunotherapy, especially using single-antibody immune checkpoint inhibitors, has shown promising efficacy against many solid cancers, and significantly improves the response rate against several solid cancers when used in combination with targeted drugs. These ad-vances will improve the survival and quality of life of many cancer patients in the near future.

study) (11). Based on this trial, the FOLFOX4 regi-men was approved by the Chinese Food and Drug Administration (CFDA) for use in first-line treatment of advanced or metastatic HCC patients in China. Besides chemotherapy, molecular target therapies have also been evaluated in clinical practice globally. In 2007, sorafenib, a tyrosine kinase inhibitor against multiple targets including RAF, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor, was shown to extend median overall survival in patients with advanced HCC, and was approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as a first-line treatment for advanced HCC. However, its use in the clinic has been limited due to low ORR, limited survival benefit, toxicity, and cost. After sorafenib, a series of molecular-targeted drugs including sunitinib, brivanib, lapatinib, linifanib, everolimus, axitinib, pazopanib, tivantinib, and ramucirumab were studied. Unfortunately, all failed in phase 3 trials. Additionally, trials combining either sorafenib with erlotinib or sorafenib with transarterial chemoembolization were also unsuccessful. In the decade since the approval of sorafenib, only two phase 3 studies, both involving multikinase inhibitors, generated positive results: regorafenib versus placebo as a second-line treatment (RESORCE study, https://www.wendangku.net/doc/d618592110.html,: NCT01774344) (12) and lenvatinib versus sorafenib as a first-line treatment (REFLECT study, https://www.wendangku.net/doc/d618592110.html,: NCT01761266) (13). Most recently, the U.S. FDA approved regorafenib for advanced HCC patients who have been previously treated with sorafenib. Lenvatinib is currently under regulatory review by FDA and EMA for first-line treatment of advanced HCC patients.

Although there are a growing number of molecular target therapies and a few cytotoxic drugs under rapid development, clinical outcomes have been unsatisfactory to date. There is a great unmet medical need for novel therapies with better response rates and survival.

Immunotherapies for HCC

Tumor immunotherapies, especially immune checkpoint inhibitors, have recently been estab-lished as effective treatments for several types of cancers. Immune checkpoint inhibitors release the “brakes” on the immune system and restore the ability of immune cells to eliminate cancer cells. Several immune checkpoint targets such as pro-grammed cell death protein 1 (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4) are being investigated exten-sively in various types of cancers. In the past few years, many clinical studies have shown immuno-therapy to be a promising treatment option for many solid tumors and hematologic malignancies. Some of these agents are now approved for the treatment of melanoma, non–small cell lung cancer, renal cell carcinoma, head and neck cancer, bladder cancer, liver cancer, gastric cancer, mismatch repair (MMR)-deficient cancer, Merkel cell carcinoma, and Hodgkin’s lymphoma.

The human liver has a unique immunobiology whereby multiple regulatory mechanisms are

in place to maintain an immunosuppressive environment. Normal liver tissue is inherently tolerogenic to environmental autoantigens and toxins in order to prevent aberrant immunity

to pathogens encountered through arterial circulation and from the gut (14, 15). Clinical and nonclinical data showed increased numbers

of immunosuppressive cells in HCC, including regulatory T cells and myeloid-derived suppressor cells, as well as increased expression of inhibitory signaling molecules such as CTLA-4 and PD-1 (16–18). HBV and HCV infections have also been associated with the increased proliferation of regulatory T cells and upregulation of PD-L1/

PD-1 expression, thereby suggesting a role

for this pathway in HBV or HCV-mediated hepatocarcinogenesis (15, 18–21). Overexpression of PD-L1 or PD-L2 has also been shown to be associated with tumor aggressiveness, disease progression, and high mortality in HCC patients (17, 22). Therefore, therapeutic agents that target immune checkpoints may potentially improve clinical outcomes by reversing the immunosuppressive nature of the HCC tumors and stimulating host immunity against the tumor cells. Interestingly, encouraging antitumor activity has now been reported in several clinical studies with anti-CTLA-4, anti-PD-1, and anti-PD-L1 antibodies. Tremelimumab is a fully humanized immuno-globulin G2 (IgG2) monoclonal antibody that blocks CTLA-4. In a phase 2 study reported in 2013, of 21 HCV-positive patients, 17 were assess-able for tumor response (23). The tumors shrank or disappeared in three patients (17.6%), and the disease control rate was 76.4%, with a median time to progression of 6.48 months. This study provided the first evidence of the antitumor activities of im-mune checkpoint inhibitors in HCC, and greatly en-couraged further investigations and clinical trials. Several anti-PD-1 antibodies are currently being evaluated in HCC patients globally. In September

CURRENT STATUS OF IMMUNOTHERAPY IN ADVANCED HCC 15

16 PRECISION MEDICINE AND CANCER IMMUNOLOGY IN CHINA

2017, the U.S. FDA approved nivolumab for the treatment of patients with HCC who have been previously treated with sorafenib. Accelerated approval for this indication was granted based on the tumor response rate and durability of response observed in the CheckMate-040 trial (24). In this trial, 14.3% [95% confidence interval (CI): 9.2–20.8; 22/154] of patients responded

to treatment with nivolumab. The percentage

of patients with a complete response was

1.9% (3/154), and the percentage with a partial response was 1

2.3% (19/154). Among responders (n=22), duration of response ranged from

3.2

to 38.2+ months; 91% of those patients had responses lasting six months or longer and 55% had responses lasting 12 months or longer. The median time to response was 2.8 months (range: 1.2–7.0). The overall response rate (based on modified RECIST) criteria was 18.2% (95% CI: 12.4–25.2; 28/154). Complete response rate was 3.2% (5/154) and partial response rate was 14.9% (23/154), also based on modified RECIST criteria. A phase 3 randomized trial (CheckMate-459) is now ongoing to assess the clinical activity of nivolumab versus sorafenib in first-line HCC treatment (https://www.wendangku.net/doc/d618592110.html,: NCT02576509) (25). Another anti-PD-1 antibody, pembrolizumab, is also under investigation for treatment of HCC patients. The KEYNOTE-240 study is a phase 3 study to assess pembrolizumab versus placebo plus best support care as a potential second-line therapy in patients with previously systemically treated advanced HCC (https://www.wendangku.net/doc/d618592110.html,: NCT02702401) (26). This study is currently ongoing.

In addition to anti-PD-1 antibodies, anti-PD-L1 antibodies are also being evaluated in HCC pa-tients. A phase 1/2 clinical trial of durvalumab in predominantly sorafenib-pretreated HCC patients showed an ORR of 10%, with a median OS of 13.2 months and a well-tolerated safety profile (https://www.wendangku.net/doc/d618592110.html,: NCT01693562) (27). A separate phase 1/2 study of durvalumab in combination with tremelimumab in unresectable HCC showed an ORR of 25%, with no unexpected safety signals (https://www.wendangku.net/doc/d618592110.html,: NCT02519348) (28). Overall, the trial demonstrated that a regimen of durvalumab plus tremelimumab was well-tolerated in this unre-sectable HCC patient population.

Many combinations of immunotherapies with molecularly targeted therapies are being evalu-ated in advanced HCC patients. Examples in-clude pembrolizumab/lenvatinib (ClinicalTrials. gov: NCT03006926) (29), nivolumab/galunisertib (https://www.wendangku.net/doc/d618592110.html,: NCT02423343) (30), nivolumab/yttrium Y 90 glass microspheres (https://www.wendangku.net/doc/d618592110.html,: NCT02837029)(31), and nivolumab/cabozantinib (https://www.wendangku.net/doc/d618592110.html,: NCT 01658878)(32).

In addition to checkpoint inhibitors, chimeric antigen receptor T cell (CAR-T) therapy has also made significant progress in the field of cancer immunotherapy. Remarkable clinical outcomes have been shown with CAR-T treatment, especially CD-19–directed CAR-T in various hematologic malignancies (33). However, to date, the clinical activity of adoptive CAR-T treatment in solid tumors has been less impressive. In HCC, CAR-T therapies targeting various antigens, including CEA, MUC1, GPC3, EGFR, EpCAM, and CD133, are under investigation in early stage clinical trials (34).

Immunotherapies for HCC in China

HCC remains a cancer with a high mortality rate and a clear unmet medical need in China, despite the fact that multiple HCC prevention programs supported by the Chinese government have been in place for many years (35, 36). Based on data retrieved from the China National Central Can-cer Registry, estimated new cases of liver cancer numbered about 356,000 in China in 2011, and the incidence rate was 26.39 per 100,000. There was also an increasing trend in the incidence rate of liver cancer in China from 2000 to 2011. As a result, the burden of liver cancer is still very high in China (37). Development of effective therapies for HCC patients remains a big challenge and an important unmet medical need.

With the boom in the Chinese biotech industry over the past five years, several China-based biopharmaceutical companies have been actively developing innovative immuno-oncology drugs for the treatment of cancers, including HCC. BGB-A317, developed by BeiGene, is an anti-

PD-1 antibody engineered to minimize Fc-gamma receptor binding on macrophages, with the aim

of abrogating antibody-dependent phagocytosis, a potential mechanism of T-cell clearance. Results from its ongoing phase 1 study were recently reported (38). At the time of data cutoff, 40 patients with unresectable HCC had been enrolled.

A majority (85%) of these patients were infected with HBV. The median treatment duration was 64 days, with a range of 1 to 471 days. BGB-A317 was well tolerated: Twenty evaluable patients remained on the treatment at the data cutoff date; partial responses were observed in three patients (all HBV-positive) and nine patients achieved stable diseases, some of whom also had significant reductions in

α-fetoprotein (AFP) levels, which indicates a positive

treatment response. Based on these initial results, a randomized, open-label, multicenter phase 3 study has been initiated to assess the efficacy and safety of BGB-A317 versus sorafenib in first-line patients with unresectable HCC.

In addition, SHR-1210, a humanized anti-PD-1 IgG4 antibody developed by Jiangsu Hengrui Pharmaceutical Co., is under investigation either as a single agent or in combination with apatinib or FOLFOX4 in HCC. There are also at least 15 other anti-PD-1 and anti-PD-L1 antibodies from different pharmaceutical companies that have either received authorization from CFDA or are currently under review to initiate clinical studies in China (39).

Glypican 3 (GPC3), a member of the glypican family of heparan sulfate proteoglycans, is high-

ly expressed on the surface of liver cancer cells with minimal expression on normal tissues (40). A clinical trial was initiated by Chinese investigators from Renji Hospital in collaboration with CARsgen Therapeutics to investigate GPC3-targeted CAR-T in Chinese patients with GPC3-positive refractory or relapsed HCC. Its preliminary phase 1 results showed that GPC3-targeted CAR-T was well tol-erated in 13 Chinese patients with GPC3-positive HCC (41). Of these 13 patients, eight were treat-ed with lymphodepleting conditioning (LDC) at baseline. Among these eight patients, there was one partial response, three showed stable diseas-es, two had progressive diseases, and two were unevaluable. Taken together, GPC3-positive CAR-T therapy showed encouraging preliminary clinical activity in Chinese patients with advanced HCC.

Conclusions

HCC remains one of the most devastating malig-nancies in the world, and a disease with significant unmet medical need, particularly in China. Immu-notherapies, especially immune checkpoint inhibi-tors, have demonstrated preliminary but promising clinical activity in patients with HCC, and several large randomized phase 3 clinical trials of these treatments are currently underway. Despite the limited progress and challenges in the development of HCC treatment in the past decades, there is hope on the horizon. With the joint efforts of pharmaceu-tical companies and academic institutions, we look forward to the continuous development of safer, more effective treatments for patients with advanced or metastatic HCC.

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CURRENT STATUS OF IMMUNOTHERAPY IN ADVANCED HCC 17

PRECISION MEDICINE AND CANCER IMMUNOLOGY IN CHINA

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China *

Corresponding author: linshenpku@https://www.wendangku.net/doc/d618592110.html,

Challenges and prospects for precision cancer

immunotherapy in China

Zhihao Lu, Jianling Zou, Shuang Li, and Lin Shen *

ith increasing incidence and mortality,

cancer has become a major public health problem in China (1). Surgery, radiotherapy, chemotherapy, and targeted therapy remain standards of care for cancer patients. However, the effectiveness of these treatments is not completely satisfactory. The success of immunotherapy, especially anti-PD-1/PD-L1 treatment, which blocks the ability of tumor cells to shield themselves from attack by the immune system, has led to some important strides in cancer care in recent years. At the same time, immunotherapy has become a hot area in cancer research and treatment in China. Here, we discuss the challenges and prospects for precision immunotherapy in the treatment of cancer, based on the unique characteristics of the Chinese population.Current status of cancer immunotherapy

Chinese pharmaceutical companies and research-ers are highly motivated to explore new immuno-therapy agents and therapies. Even though no PD-1 or PD-L1 inhibitor has yet been approved by the Chinese Food and Drug Administration (CFDA), the Chinese government is making earnest efforts to im-prove the overall clinical research environment, and the CFDA is actively reforming the regulatory frame-work to accelerate approval of novel agents (2). By July 2017, Chinese pharmaceutical companies had developed 10 anti-PD-1/PD-L1 inhibitors, eight of which have been approved by CFDA for phase 1 to phase 3 clinical trials in patients with advanced solid tumors (Table 1). In November 2016, clinical trials of PD-1 inhibitor KN035 were approved by the U.S. Food and Drug Administration (FDA) (3). In the past five years, around 1,000 international clinical trials of PD-1/PD-L1 therapies for solid tumors have been registered in the https://www.wendangku.net/doc/d618592110.html, database, of which 100 involved Chinese sites (2). Thus, Chinese

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