Using Low-dose Radiation,SHP-2 Inhibition To Increase The Treatment Efficacy Of Radiotherapy Combined With Immunotherapy(iRT):A Clinical And Academic Study

Background:Approximately one-half of patients with newly diagnosed cancer and many patients with persistent or recurrent tumors receive radiotherapy(RT),with the explicit goal of eliminating tumors through direct killing.The current RT dose and schedule regimens have been empirically developed.Although early clinical studies revealed that RT could provoke important responses not only at the site of treatment but also on remote,nonirradiated tumor deposits—the so-called "abscopal effect"—the underlying mechanisms were poorly understood and were not therapeutically exploited.Recent work has elucidated the immune mechanisms underlying these effects and has paved the way for developing combinations of RT with immune therapy.In the wake of recent therapeutic breakthroughs in the field of immunotherapy,rational combinations of immunotherapy with RT could profoundly change the standard of care for many tumor types in the next decade.Thus,a deep understanding of the immunologic effects of RT is urgently needed to design the next generation of therapeutic combinations.Here,the authors review the immune mechanisms of tumor radiation and summarize the preclinical and clinical evidence on immunotherapy-RT combinations.Furthermore,a framework is provided for the practicing clinician and the clinician investigator to guide the development of novel combinations to more rapidly advance this important field.We posted a hypothesis that radiotherapy could overcome immunotherapy resistance and increase the treatment efficacy.So,we focused on three parts in this manuscript:1.Exploring whether adding radiotherapy could increase treatment efficacy of pembrolizumab in clinical level;2.Low-dose irradiation could boost the abscopal effect when using high-dose irradiation with immunotherapy;3.Using SHP-2 inhibitor to increase the treatment efficacy of radiotherapy with immunotherapy.Part 1:Radiotherapy Combined With Immunotherapy(iRT)Increased Responses and Outcomes:Pooled Analysis of Two Phase 2 Randomized TrialsIntroductionIn metastatic non-small cell lung cancer(mNSCLC),the clinical trials NCT02492568 and NCT02444741 are the only known randomized comparisons of pembrolizumab alone versus pembrolizumab combined with radiation therapy(RT).When the trials were analyzed individually,some potential benefit was observed in the combination therapy group,but the relatively small sample size of each trial limited the detection of potential differences in response rates and outcomes.Hence,we perform a pooled analysis of these two randomized trials to validate and explore whether this synergistic effect exist in mNSCLC.MethodsThis was a pooled analysis of two randomized trials(NCT02492568 and NCT02444741)of pembrolizumab with or without RT for mNSCLC.All patients from either trial treated per protocol with adequate imaging follow-up and no RT 6 months prior to enrollment were included.Endpoints included the abscopal response rate(ARR)and abscopal control rate(ACR),which were based on Response Evaluation Criteria in Solid Tumors,progression-free survival(PFS),overall survival(OS),and subgroup analysis of the different RT schemes.ResultsIn all,146 patients were analyzed(n=76 pembrolizumab;n=72 pembrolizumab/RT(iRT)).ARR was 19.7%in the pembrolizumab arm VS.41.7%in the iRT arm(p=0.004);ACR was 43.4%in the pembrolizumab arm VS.65.2%in the iRT arm(p=0.0087);PFS was 4.4 m VS 9.0 m(p=0.026);and OS was 8.7 m VS 19.2 m(HR 0.66;p=0.006).Ablative RT(24Gy/3 fractions and 50Gy/4 fractions)had ORRs of 47.2%and 56.2%,respectively,compared to 20%for non-ablative RT(45Gy/15 fractions)and 19.7%for pembrolizumab alone(p<0.05 for all).ConclusionThe addition of RT to immunotherapy significantly increased the ORR of unirradiated lesions and was additionally associated with significant improvements in PFS and OS.These hypothesis-generating findings require dedicated,large-volume,and randomized studies for corroboration.Part 2:Using Low-Dose Radiation to enhance the treatment efficacy of iRTIntroductionPreclinical evidence suggests that low-dose radiation may overcome the inhibitory effects of the tumor stroma and improve a tumor's response to immunotherapy,when combined with Stereotactic Body Radiation Therapy(SBRT)to another tumor.The aim of this study was to evaluate tumor responses to this combination in a clinical setting.MethodsA post-hoc analysis of 3 ongoing immunoradiation trials was performed.Twenty-six(of 155)patients received low-dose radiation(1-20 Gy total),either as scatter from high-dose radiation or from intentional treatment of a second isocenter with low-dose radiation,were evaluated for response.The low-dose lesions were compared to lesions that received no radiation(<1 Gy total).Response rates defined as complete and partial responses as defined by RECIST 1.1 criteria were used to compare lesion types.ResultsThe 26 patients had a total of 83 lesions for comparison(38 receiving low-dose,45 receiving no-dose).The average dose given to low-dose lesions was 7.3 Gy(1.1-19.4 Gy),and the median time to response was 39 days.Twenty out of 38(53%)low-dose lesions met the PR/CR criteria for RECIST compared with 8 out of 45(18%)no-dose lesions(p=0.001).Among the low-dose lesions that had at least one no-dose lesion within the same patient as a control(33 and 45 lesions respectively),14 low-dose lesions(42%)responded without a corresponding response in their no-dose lesions.Conversely,none of the no-dose lesions responded without a corresponding response in their low-dose lesion.ConclusionsLow-dose radiation may increase systemic response rates of metastatic disease treated with high-dose radiation and immunotherapy.Part 3:Using SHP-2 inhibition to enhance the treatment efficacy of iRT in ananti-PD-1-resistant modelIntroductionImmune checkpoint inhibitors such as Anti-PD-1/PD-L1 have emerged as promising therapies for advanced non-small-cell-lung cancer(NSCLC).However,approximately 80%of patients do not respond to immunotherapy given alone because of intrinsic or acquired resistance.Radiotherapy(XRT)can overcome PD-1 resistance and improve treatment outcomes,but its efficacy remains suboptimal.The tyrosine phosphatase SHP-2,expressed in some cancers and in immune cells,has been shown to negatively affect Anti-tumor immunity.Our hypothesis was that SHP-2 inhibition in combination with ?-PD-L1 would enhance immune-mediated responses to XRT and synergistically boost Anti-tumor effects in an Anti-PD-1-resistant mouse model.MethodsWe treated 129Sv/Ev mice with Anti-PD-1-resistant 344SQ NSCLC adenocarcinoma xenografts with oral SHP099(an SHP-2 inhibitor)combined with XRT and intraperitoneal ?-PD-L1.Primary tumors were treated with XRT(3 fractions of 12 Gy each),whereas abscopal(out-of-field)tumors were observed but not treated.ResultsXRT in combination with SHP099 and ?-PD-L1 promoted local and abscopal responses,reduced lung metastases,and improved mouse survival.XRT also increased SHP-2+Ml tumor-associated-macrophages in abscopal tumors(p=0.019).The addition of SHP099 was also associated with higher M1/M2 ratio,greater numbers of CD8+T sphorylation inhibitor overcomes PD-1 resistancells,and fewer regulatory T cells.ConclusionThis novel triple-combination therapy had strong Anti-tumor effects in this mouse model of Anti-PD-1-resistant NSCLC and may be a novel therapeutic approach for Anti-PD-1-resistant NSCLC in patients.