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Introductions

3Foundationalbiomarkers for

precisionmedicine

SeanSanders,Ph.D.

JackieOberst,Ph.D.

Scie n ce/AAAS

4Aglobaloncologycompanyrooted

in China

Xia odongWang,Ph.D.

Fou nder&ChairmanofScientificAdvisoryBoard,BeiGene

Joh nV.Oyler

Fou nder&CEO,BeiGene

Articles

5Tar g etedtherapyforlivercancer:

Challengesandopportunities

Shu zhenChen,JingFu,andHongyangWang

9The c hallengesofradiationoncology

intheeraofprecisionmedicine

Lig angXingandJinming Yu

12The r oleofmultidisciplinaryeffortsin

precisionmedicineandimmunologyfor

clinicaloncology

Jia nzhenLin,AnqiangWang,JunyuLong etal.

14C u r r entstatusofimmunotherapyin

advancedHCC

Shu kuiQin

18Challengesandprospectsforprecision

cancerimmunotherapyinChina

Zhi haoLu,JianlingZou,ShuangLi etal.

24Theriseofengineered T-celltherapy

inChina

Jia nshuWei,YiZhang,andWeidongHan Precision

medicine

and cancer

immunology

inChina

TABLEOFCONTENTS

TAB LEOFCONTENTSCONTINUED>

2PRECISION MEDICINE AND CANCER IMMUNOLOGY IN CHINA

Precision medicine and cancer 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Materials that appear in this supplement have not been peer-reviewed nor have they been assessed by Science.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]. Xiaoying Chu

Director, Global Collaboration and

Business Development, Asia

xchu@https://www.wendangku.net/doc/aa4303956.html, +86-131-6136-3212

Danny Zhao

Regional Sales Manager, Asia

dzhao@https://www.wendangku.net/doc/aa4303956.html, +86-131-4114-0012

2 February 2018Articles continued

29Precision cancer medicine and immunology in China Xu-Chao Zhang and Yi-Long Wu

35From big data to knowledge in precision medicine Dechao Bu, Shaoliang Peng, Haitao Luo et al.

38The role of circulating cell-free DNA in the management of cancer in China Ying Hu, Yanhui Chen, Lei Zhang et al.

44Next-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.

49ctDNA-NGS: The key to unlocking a molecular diagnostic revolution in the

heart of Asia

Ying Hou and Kang Ying

52Adoptive cell transfer therapy: A strategic

rethinking of combination

cancer therapy

Minghui Zhang

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

next-generation DNA sequencing (genomics), analysis of protein levels in blood or tissues (proteomics), or determination of RNA levels

(transcriptomics). However, identifying and characterizing biomarkers that

accurately 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

forward 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 probability

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-quality 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

INTRODUCTION

ne might argue that the concept of personalized medicine—in which a treatment is tailored for a specific individual

based on their unique physiology as well as their specific disease

and drug 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-

Foundational z ation of the patient is necessary. Various biomarkers provide the necessary data, collected throug variety of 'omics techniques including

4PRECISION MEDICINE AND CANCER IMMUNOLOGY IN CHINA

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

eiGene, Ltd. (NASDAQ: BGNE) is a global, commercial-stage

biotechnology company focused on molecularly targeted and immuno-oncology cancer therapies. With a team of over 800 employees in China, the United States, and Australia,

BeiGene is advancing a pipeline of novel small molecules, monoclonal

global oncology company rooted in China

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.

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 Biologic al 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 company has domestic manufacturing capabilities, including a multipurpose manufacturing facility in

Suzhou and a commercial-scale biologics manufacturing facility under construction in Guangzhou, established through a joint venture with the Guangzhou

Development District. Through its strategic collaboration with Celgene, BeiGene also recently acquired Celgene’s commercial operations in China and gained exclusive rights to commercialize 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. Targeted therapy for liver cancer:

Challenges and opportunities

Shuzhen

Che

n1,23,

Jing

Fu1,

2?,

and

Hon

gya

ng1,

24* 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

1 International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary

Surgery Institute, Second Military Medical University, Shanghai, China

2 National Center for Liver Cancer, Shanghai, China

3 Joint first author

4 Corresponding author: hywangk@https://www.wendangku.net/doc/aa4303956.html, were diagnosed in China and 422,100 deaths occurred 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 technology such as next-generation DNA sequencing has enabled a rapid and dramatic increase in our understanding of the genetic, molecular, and morphological 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 targeted therapy will provide functional and even structural corrections at the molecular level, or at least offer a valid alternative to conventional treatment. However, liver cancer is an extraordinarily heterogeneous disease, which makes it difficult to properly stratify patients for optimal targeted treatment and increases 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 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 intracellular 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 randomized trial conducted in the Asia-Pacific region. According to these two studies, the sorafenib treatment 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 gastrointestinal, 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 revealed 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 underlying resistance to sorafenib and to identify potential biomarkers TARGETED THERAPY FOR LIVER CANCER: CHALLENGES AND OPPORTUNITIES

6PRECISION MEDICINE AND CANCER IMMUNOLOGY IN CHINA

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 sorafenib 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 median survival time reduced by more than 40 months (p=0.0099). These results suggest that PSMD10 may be a potential molecular marker in the classification of HCC patients who may not respond effectively 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 administration 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 chemotherapeutic strategies (18). The varied cellular metabolic phenotypes of tumor cells may also affect the efficacy of sorafenib. Investigation 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 carboxylase alpha (ACC a) enhanced glucose-derived de novo fatty acid synthesis (FAS) and promoted tumor cell survival under energy stress, which contributed 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 interfering with ACC a-driven FAS could sensitize HCC cells to sorafenib (19). Another study has reported that blocking interleukin-6/signal transducer and activator of transcription 3 (STAT3)–mediated preferential glucose uptake could sensitize liver tumor–initiating cells to sorafenib treatment and enhance its therapeutic 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 overexpressed in 40%–70% of human HCCs, a factor that has been proven to be closely linked to the formation and growth of tumors. But EGFR inhibitors have shown disappointing results in clinical trials with unselected patients (21). A study was conducted in Taipei to evaluate the efficacy and safety of vandetanib, an oral inhibitor of both VEGFR and EGFR, in patients with inoperable advanced HCC. The study observed no significant difference in the rate of tumor stabilization or vascular change between the vandetanib group and the placebo group, suggesting that vandetanib had limited clinical activity in HCC (22). Other clinical trials with erlotinib, gefitinib, or cetuximab showed only limited effects in advanced stage HCC or modest effects at most in phase 2 trials (21). A better understanding of the mechanisms underlying 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, whereas mice lacking EGFR in hepatocytes unexpectedly developed more HCCs due to increased compensatory proliferation after cell damage. Following inflammatory stimulation, EGFR induces interleukin-6 expression in liver macrophages, triggering hepatocyte proliferation and the development of HCC (23). This study demonstrated that EGFR has different roles in tumor cells than in nontumor cells, providing 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 mammalian 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 hepatocytes, 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-

7 derived antibody or peptide

vaccines has been explored in HCC

immunotherapy (27–29).

Disappointingly, in clinical trials

these agents showed only limited

curative 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 GPC3positive

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

8PRECISION MEDICINE AND CANCER IMMUNOLOGY IN CHINA

TARGETED THERAPY FOR LIVER CANCER: CHALLENGES AND OPPORTUNITIES

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/L1

Programmed 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 inhibitor nivolumab in patients with advanced HCC in 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 previous reports, it has been

anopen-label,

noncomparative,

phase1/2dose

escalationand

expansiontrial.

Thestudyshowed

thatnivolumab

produceddurable

objectiverespons-

esinlong-term

survivalratesin

patientswithad-

vancedHCC(37).

However, it

isimportantto

recognizethatin

previousstudies

theresponserate

toanti-PD-1asa

stand-alonether-

apywas10%–30%

overall, which

includedimmu-

nogenictumors

suchasmalignant

melanomathat

haveamuchhigh-

erresponserate

( 36. Onepossible

)

explanationfor

thelowresponse

ratemightbe

theinfluenceof

moleculesin-

volvedinimmune

escapeotherthan

FIGURE1.Schematicrepresentationofthesignalingnetworkandagentsinvolvedintargetedtherapy forlivercancer.ErlotinibandgefitinibaretyrosinekinaseinhibitorstargetingEGFR.ThePI3K/AKT/

mTOR/p70S6andRas/Raf/MEK/ERKpathwaysareinvolvedwhenEGFRsignalingisactivated,andcan beblockedbyindependentinhibitors.Vandetanibandsorafenibaremultikinaseinhibitorsofseveral tyrosineproteinkinasessuchasVEGFRandPDGFR.GPC3increasesthebindingofWnttoFZD,which resultsinthestimulationof b catenintranscriptionalactivity.ApproachestotargetingGPC3inHCCsuch

asanti-GPC3antibodyorGPC3-targetedchimericantigenreceptorhaveshownsomepromiseindiffer-entstudies.EGFR,epidermalgrowthfactorreceptor;PDGFR,platelet-derivedgrowthfactorreceptor;

GPC3,glypican-3;Ab,antibody;VEGFR,vascularendothelialgrowthfactorreceptor;PI3K,phosphati-dylinositol-3kinase;mTOR,mammaliantargetofrapamycin;p70S6,ribosomalproteinS6kinase;MEK, MAPK/ERKkinase;MAPK,mitogen-activatedproteinkinase;ERK,extracellularsignal-regulatedkinase; DSH,dishevelled;FZD,frizzled;HIF-1a,hypoxia-induciblefactor1-alpha.

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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NCER IMMUNOLOGY IN CHINA

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 di scoveries 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), intensitymodulated 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/aa4303956.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

THE CHALLENGES OF RADIATION ONCOLOGY IN THE ERA OF PRECISION MEDICINE

11 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

12PRECISION 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 patients 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 medicine, 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 noninvasive measurements of functional and physiological properties of tissues and lesions at the molecular level. The development and application of molecular imaging techniques brings new opportunities for creating more precise treatment.

THE CHALLENGES OF RADIATION ONCOLOGY IN THE ERA OF PRECISION MEDICINE

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) scanallowed clinicians to deliver higherdose 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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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 role of multidisciplinary

efforts in precision medicine

and immunology for clinical oncology