Abscopal Response Rates Research Articles

Phase I/II study of BMS-986156 with ipilimumab or nivolumab with or without stereotactic ablative radiotherapy in patients with advanced solid malignancies

BackgroundBMS-986156 is an agonist of the glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) and promotes increased effector T-cell activation. Combined anti-GITR, anti-programmed death-1, anti-cytotoxic T-lymphocyte-associated protein 4 antibodies and...

Sintilimab in combination with stereotactic body radiotherapy and granulocyte-macrophage colony-stimulating factor in metastatic non-small cell lung cancer: The multicenter SWORD phase 2 trial

This single-arm, multicenter, phase 2 trial (NCT04106180) investigated the triple combination of sintilimab (anti-PD1 antibody), stereotactic body radiotherapy (SBRT) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in metastatic non-small cell lung cancer (NSCLC). With a median follow-up of 32.1 months, 18 (36.7%, 90% CI 25.3%–49.5%) of the 49 evaluable patients had an objective response, meeting the primary endpoint. Secondary endpoints included out-of-field (abscopal) response rate (ASR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). The ASR was 30.6% (95% CI 18.3%–45.4%). The median PFS and OS were 5.9 (95% CI 2.5–9.3) and 18.4 (95% CI 9.7–27.1) months, respectively. Any grade and grade 3 TRAEs occurred in 44 (86.3%) and 6 (11.8%) patients, without grade 4–5 TRAEs. Moreover, in pre-specified biomarker analyses, SBRT-induced increase of follicular helper T cells (Tfh) in unirradiated tumor lesions and patient’s blood, as well as of circulating IL-21 levels, was found associated with improved prognosis. Taken together, the triple combination therapy was well tolerated with promising efficacy and Tfh may play a critical role in SBRT-triggered anti-tumor immunity in metastatic NSCLC.

Novel time-synchronized immune-guided partial tumor irradiation: Proof of principle trial

Background and purposeRadiotherapy for bulky tumors often results in palliation with suboptimal outcomes. The prognosis is worsened by immunosuppression caused by radio-chemotherapy, negatively impacting on survival. Novel Partial Tumor Irradiation (PTI) was designed to spare the Peritumoral Immune Microenvironment (PIM) and to be delivered synchronously with immune activity peaks, thus enhancing both local and distant tumor control through immunostimulation. Materials and methodsPresent proof-of-principle trial enrolled 26 patients with bulky tumors, comparing outcomes between treatments administered at immune activity peaks versus troughs. The primary endpoint was local-bystander and distal-abscopal response-rate. Secondary endpoints included overall-, progression-free-, cancer-specific survival, neoadjuvant and immunomodulatory potential. ResultsAll measured outcomes were significantly influenced by treatment-timing. The bystander and abscopal response rates were 77% and 41%, respectively. PTI significantly upregulated pro-inflammatory and cell-death-inducing pathways improving the efficacy of radiotherapy by highly complex tumors. ConclusionsThis study highlights the profound impact PTI can have on a highly palliative patient cohort previously deemed beyond therapeutic hope. With 41 % of these patients still alive after a median follow-up of 50 months, PTI offers a potential lifeline for those facing advanced, treatment-resistant cancers. This approach generated also distant immunogenic anti-tumor responses, offering a promising new avenue for the treatment of advanced cancers.

Challenges in synergizing radiotherapy with immunotherapy to unlock the abscopal effect in metastatic NSCLC: A systematic review

BackgroundWith the recent success of immunotherapy, there is a growing interest in combining radiation with immunotherapy to boost abscopal response rates. Several challenges exist in determining how to synergize these two modalities in the treatment of metastatic NSCLC. MethodsReferences for this review were identified through searches of MEDLINE/PubMed and Clinicaltrials.gov databases with the search terms “abscopal”, “radiation OR radiotherapy,” “NSCLC”, and “lung” on the index date of July 2022 from 2000-2022. This systematic review focuses primarily on clinical papers. DiscussionEarly work combining radiotherapy with immunotherapy show promise in unlocking the abscopal effect. Preliminary evidence suggests that radiotherapy regimens with <5 fractions and smaller fields may be superior to regimens with 15 fractions and larger fields. There does not appear to be enough evidence to draw conclusions about the optimal timing of radiotherapy in relation to immunotherapy or the optimal anatomical location of radiation to induce the abscopal effect. Several studies suggest selecting patients with a higher absolute lymphocyte count (ALC) and lower neutrophil-to-lymphocyte ratio (NLR) may help to further boost abscopal response rates. Furthermore, selecting tumors with programmed death ligand-1 (PD-L1) expression, mismatch repair deficiency, and higher tumor mutational burden may similarly achieve this goal. Lastly, additional work is needed to minimize and predict for severe toxicity associated with combination therapy.

Radiotherapy plus camrelizumab and irinotecan for oligometastatic esophageal squamous cell carcinoma patients after first-line immunotherapy plus chemotherapy failure: An open-label, single-arm, phase II trial

Background and purposeImmunotherapy has revolutionized the treatment of advanced and metastatic esophageal squamous cell carcinoma (ESCC), but most patients eventually developed disease progression. Immuno-resistance is becoming an unavoidable clinical problem. Oligometastasis is a limited-metastatic state, and patients at this stage should be evaluated for the addition of metastasis-directed local intervention, which may be associated with improved prognosis. As an immunomodulator, radiotherapy may exhibit synergistic effect when added to immunotherapy. This study assessed the efficacy and safety of low-dose radiotherapy plus immunotherapy and second-line chemotherapy in oligometastatic ESCC. Materials and methodsIn this phase II trial (ChiCTR2000040533), oligometastatic ESCC patients after first-line immunotherapy plus chemotherapy failure were treated with low dose radiotherapy plus camrelizumab and second-line irinotecan chemotherapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), and safety. Abscopal response rate (ARR) and abscopal control rate (ACR) were also been explored. ResultsBetween November 19, 2018 and March 17, 2021, 49 patients were enrolled. With a median follow-up of 12.8 months, median PFS and OS were 6.9 months (95%CI, 4.6–9.3) and 12.8 months (95%CI, 10.1–15.5), respectively. ORR was 40.8% (95%CI, 27.3–55.7). DCR was 75.5% (95%CI, 60.8–86.2). ARR was 34.7% (95%CI, 22.1–49.7). ACR was 69.4% (95%CI, 54.4–81.3). The most common adverse effects of any grade were myelosuppression, weight loss and fatigue. Grade 3 or 4 treatment-related adverse events occurred in 31 (63.3%) patients, with the most common being leukopenia (30.6%). No treatment-related deaths occurred. ConclusionLow dose radiotherapy plus camrelizumab and irinotecan exhibited survival benefit with manageable safety for oligometastatic ESCC patients after first-line immunotherapy plus chemotherapy failure. It deserves to be validated in a larger trial.

Combined treatment of non‐small cell lung cancer using radiotherapy and immunotherapy: challenges and updates

The efficacy of immunotherapy for advanced non‐small cell lung cancer (NSCLC) remains unsatisfactory, as the majority of patients either do not experience an objective response or acquire secondary resistance. As a result, several methods to enhance the systemic efficacy of immunotherapy have been investigated, including a large area of active research by combining immunotherapy with radiation therapy (RT). Given the rapidly burgeoning concept of combining immunotherapy and RT for increasing therapeutic benefit, we review the progress in this field thus far and explore further avenues for enhancing this combination. This review commences with a discussion of the only two existing randomized trials (and a pooled analysis) showing that the addition of RT to immunotherapy improves the abscopal response rate, progression‐free survival, and overall survival in metastatic NSCLC patients. We then discussed factors and biomarkers that may be associated with a proportionally greater benefit to additional RT, such as low programmed cell death protein ligand 1 (PD‐L1) status, tumor mutational burden (TMB), and patient's immune function. Next, the implementation of RT to overcome immunotherapy resistance is discussed, including a mechanistic discussion and methods with which these mechanisms could be exploited. Lastly, the emerging role of low‐dose RT is discussed, which may help to overcome inhibitory signals in the tumor stroma that limit T‐cell infiltration. Taken together, given the current state of this rapidly expanding realm, these futuristic strategies may be reflected upon to further enhance the efficacy of immunotherapy for a wider group of patients.

High Rate of Abscopal Regression of Follicular Lymphoma after Low Dose Involved-Site Radiation Therapy Detected by FDG-PET Scans

We conducted a retrospective analysis to estimate the frequency of abscopal regression of follicular lymphoma (FL), detected by FDG-PET/CT scanning. Potential cases were identified from an institutional radiation therapy database. All FL patients treated with palliative involved site radiation therapy (ISRT) in a 3-year period were systematically reviewed. The cases of abscopal regression reported here met the following criteria. a) Palliative ISRT given for histologically confirmed FL b) >2 lesions visualized on FDG-PET c) >1 un-irradiated lesion(s) outside ISRT volume d) no systemic therapy <2 months before RT or between RT and response assessment, e) complete metabolic response (CMR) in >1 unirradiated lesions detected on serial FDG-PET/CT. Four cases of abscopal regression of FL were identified between January 2016 to December 2018. In all cases a CMR was apparent both within the ISRT volume and in >1 unirradiated lesions. During the study period, 29 ISRT courses were prescribed for multifocal FL, following which 4/29 (13.8%) abscopal responses were observed. Treatment received was either 4Gy in 2 fractions, (n = 3) or 4Gy followed 8 months later by 30Gy in 15 fractions (n = 1). Sites irradiated were abdominal lymph nodes (n = 1) neck node (n = 1), lower leg soft tissue (n = 1) and epitrochlear node (n = 1). In 3 cases a CMR was observed at all disease sites. In one case a CMR was observed only at some disease sites. If all 29 ISRT courses, where some disease sites were not irradiated are considered to be the denominator, the rate of abscopal response in FL was 4/29 (13.8%). If only the 14 courses where no systemic therapy was given and wide-field of view imaging was performed that could potentially have detected abscopal regression are considered, the abscopal response rate was 4/14 (28.6%). If only the cases with serial FDG-PET imaging are considered, the abscopal response rate was 4/9 (44.4%). The lower limit of the estimated abscopal rate was thus 13.8% (95% confidence interval (CI) 6-34%)) and the upper limit was 44.4% (95% CI 21-92%). One patient who had an allogeneic bone marrow transplantation after a complete abscopal regression of FL later relapsed and had a subsequent complete response to immunotherapy (donor lymphocyte infusion). Abscopal regression of FL may be more common than previously-suspected and can be induced by very low dose ISRT. In 3/4 cases, PET-detected abscopal regression of FL occurred after only 4Gy ISRT, and in 1/4 cases, only after a second ISRT course to the same volume. In one case, abscopal regression was associated with a subsequent complete response to immunotherapy.

A Novel Immunotherapy Strategy Incorporating Epacadostat, Intralesional SD-101, and Radiotherapy Demonstrating Activity in Checkpoint Refractory Patients

We have previously demonstrated, in mouse models and canines with spontaneous malignancies, the efficacy of a tri-modality immunotherapy strategy incorporating intralesional TLR9 agonist, local radiotherapy, and IDO blockade. Published clinical studies suggest a strong in-situ vaccination effect of combining TLR agonists and radiotherapy. Our data suggests that adding IDO inhibition significantly increases the efficacy of this in-situ vaccination by preventing “rebound immune suppression” and facilitating a robust systemic response. IRB approved protocol (NCT03322384) a phase I/II clinical trial of epacadostat, intralesional SD-101 (4mg x 5 weekly injections), and local radiotherapy (2Gy x 2, 4Gy x 5, or 8Gy x 3) for patients with advanced refractory solid tumors (cohort 1) and lymphomas (cohort 2) opened to accrual in 4/2018. The trial was designed as a phase I 3+3 dose de-escalation starting at 300 mg po bid of epacadostat. The phase II was designed as a Simon-two stage expansion for each cohort. Twenty total patients were enrolled. Using an intention-to-treat analysis we report the outcome for 7 patients refractory to prior therapy with PD-(L)1 checkpoint inhibition. In these patients, DCR and abscopal DCR was 86% (6/7) and 100% (7/7), response rate was 43% (3/7), and abscopal response rate was 29% (2/7) including 2 patients with long term durable complete responses. Patients had serial biopsies and serial blood samplings and results of intensive correlative analysis will also be reported. This is the first in human report of this novel triple therapy strategy and the first in human report of visceral intralesional injections of SD-101. This strategy appears to rescue some patients resistant to PD-(L)1 checkpoint blockade.

Abscopal Response Rates after Salvage Radiation in Patients with Progressive Disease on Immunotherapy

Abscopal Response Rates after Salvage Radiation in Patients with Progressive Disease on Immunotherapy

Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials

Radiotherapy might augment systemic antitumoral responses to immunotherapy. In the PEMBRO-RT (phase 2) and MDACC (phase 1/2) trials, patients with metastatic non-small-cell lung cancer were randomly allocated immunotherapy (pembrolizumab) with or without radiotherapy. When the trials were analysed individually, a potential benefit was noted in the combination treatment arm. However, owing to the small sample size of each trial, differences in response rates and outcomes were not statistically significant but remained clinically notable. We therefore did a pooled analysis to infer whether radiotherapy improves responses to immunotherapy in patients with metastatic non-small-cell lung cancer. Inclusion criteria for the PEMBRO-RT and MDACC trials were patients (aged ≥18 years) with metastatic non-small-cell lung cancer and at least one unirradiated lesion to monitor for out-of-field response. In the PEMBRO-RT trial, patients had previously received chemotherapy, whereas in the MDACC trial, patients could be either previously treated or newly diagnosed. Patients in both trials were immunotherapy-naive. In the PEMBRO-RT trial, patients were randomly assigned (1:1) and stratified by smoking status (<10 vs ≥10 pack-years). In the MDACC trial, patients were entered into one of two cohorts based on radiotherapy schedule feasibility and randomly assigned (1:1). Because of the nature of the intervention in the combination treatment arm, blinding to radiotherapy was not feasible in either trial. Pembrolizumab was administered intravenously (200 mg every 3 weeks) with or without radiotherapy in both trials. In the PEMBRO-RT trial, the first dose of pembrolizumab was given sequentially less than 1 week after the last dose of radiotherapy (24 Gy in three fractions), whereas in the MDACC trial, pembrolizumab was given concurrently with the first dose of radiotherapy (50 Gy in four fractions or 45 Gy in 15 fractions). Only unirradiated lesions were measured for response. The endpoints for this pooled analysis were best out-of-field (abscopal) response rate (ARR), best abscopal disease control rate (ACR), ARR at 12 weeks, ACR at 12 weeks, progression-free survival, and overall survival. The intention-to-treat populations from both trials were included in analyses. The PEMBRO-RT trial (NCT02492568) and the MDACC trial (NCT02444741) are registered with ClinicalTrials.gov. Overall, 148 patients were included in the pooled analysis, 76 of whom had been assigned pembrolizumab and 72 who had been assigned pembrolizumab plus radiotherapy. Median follow-up for all patients was 33 months (IQR 32·4-33·6). 124 (84%) of 148 patients had non-squamous histological features and 111 (75%) had previously received chemotherapy. Baseline variables did not differ between treatment groups, including PD-L1 status and metastatic disease volume. The most frequently irradiated sites were lung metastases (28 of 72 [39%]), intrathoracic lymph nodes (15 of 72 [21%]), and lung primary disease (12 of 72 [17%]). Best ARR was 19·7% (15 of 76) with pembrolizumab versus 41·7% (30 of 72) with pembrolizumab plus radiotherapy (odds ratio [OR] 2·96, 95% CI 1·42-6·20; p=0·0039), and best ACR was 43·4% (33 of 76) with pembrolizumab versus 65·3% (47 of 72) with pembrolizumab plus radiotherapy (2·51, 1·28-4·91; p=0·0071). Median progression-free survival was 4·4 months (IQR 2·9-5·9) with pembrolizumab alone versus 9·0 months (6·8-11·2) with pembrolizumab plus radiotherapy (hazard ratio [HR] 0·67, 95% CI 0·45-0·99; p=0·045), and median overall survival was 8·7 months (6·4-11·0) with pembrolizumab versus 19·2 months (14·6-23·8) with pembrolizumab plus radiotherapy (0·67, 0·54-0·84; p=0·0004). No new safety concerns were noted in the pooled analysis. Adding radiotherapy to pembrolizumab immunotherapy significantly increased responses and outcomes in patients with metastatic non-small-cell lung cancer. These results warrant validation in a randomised phase 3 trial. Merck Sharp & Dohme.

Stereotactic ablative radiotherapy for colorectal cancer liver metastasis.

Survival improvement of colorectal liver metastasis (CRLM) benefits from systemic therapy and metastasis-directed local therapy. Stereotactic ablative body radiotherapy (SABR), as a new efficient metastasis-directed local therapy with a systematic impact, plays a vital role in CRLM multidisciplinary treatment. SABR leads to a dramatic immunological change in the tumor microenvironment (TME) via differential activation of cytoprotective and cytotoxic pathways in malignant and non-malignant cells, in addition to direct tumor cell death. The synergy of SABR and immunotherapy might increase the abscopal response rate of out-field lesions by targeting different steps of the immune-mediated response, in addition to direct intratumoral cell death. The clinical treatment and efficacy of SABR, its influence on TME, and potential molecular underpinnings of which are the topic of this review.

Absolute Lymphocyte Count Predicts Abscopal Responses and Outcomes in Patients Receiving Combined Immunotherapy and Radiation Therapy: Analysis of 3 Phase 1/2 Trials

Research to elucidate predictive factors of the abscopal effect is an essential first step toward potentially modifying these factors to increase the incidence of systemic antitumor effects. This study, using data from 3 institutional phase 1/2 trials, examined the predictive capacity of recorded parameters in patients undergoing combined radiation therapy (RT) and immunotherapy and explored outcomes based on those predictive factors. All patients underwent combined immunotherapy and RT and had at least 1 nonirradiated noncontiguous lesion to evaluate out-of-field (abscopal) responses, defined as the best Response Evaluation Criteria in Solid Tumors response. Altogether, 153 patients met study criteria, and the median follow-up was 21.1 months. The most common cancer types were non-small cell lung carcinoma (n= 62), small cell lung carcinoma (n = 25), head and neck cancers (n = 16), and renal cell carcinoma (n = 13). Immunotherapies included ipilimumab (n = 98) and pembrolizumab (n = 55). Multivariable linear regression indicated that post-RT absolute lymphocyte count (ALC), when analyzed as a continuous variable, correlated with abscopal responses (P < .001). For post-RT ALC, the abscopal response rate was 34.2% in the cohort with ALC higher than the median value, compared with 3.9% in patients with ALC lower than the median (P < .0001). Corresponding figures for pre-RT ALC were 30.3% versus 7.8%, respectively (P = .0004). Cox multivariate analysis confirmed that lower post-RT ALC also associated with poorer progression-free survival (P = .009) and overall survival (P = .026). Lymphopenia, measured as the continuous variable of post-RT ALC, may affect the occurrence of abscopal responses and thus influence prognosis in patients treated with RT and immunotherapy. Although this hypothesis-generating finding requires corroboration by additional data, it suggests the importance of ALC monitoring and the potential of therapeutic manipulation of this parameter to induce abscopal effects.

Abscopal Effect of Radiotherapy and Nivolumab in Relapsed or Refractory Hodgkin Lymphoma (AERN): An International Multicenter Single-Arm Two-Stage Phase II GHSG Trial

Abscopal Effect of Radiotherapy and Nivolumab in Relapsed or Refractory Hodgkin Lymphoma (AERN): An International Multicenter Single-Arm Two-Stage Phase II GHSG Trial

The systemic immunostimulatory effects of radiation therapy producing overall tumor control through the abscopal effect

Emerging studies show that radiation therapy produces an important out of field (distant) effect known as the ‘‘abscopal effect” in nonirradiated tumor sites. The objective of this study was to provide an overview of the current state of knowledge and clinical experience of radiation therapy producing abscopal effects in the management of different types of malignant diseases. Peer-reviewed published clinical evidence on the abscopal effect of radiation therapy was collected using electronic databases such as Medline via PubMed and Google Scholar. The reference lists were searched in the publications that we obtained in an attempt to find additional relevant publications. Non-indexed peer-reviewed journals were manually searched and relevant information was extracted. The search was restricted to English language articles. The clinical data on the abscopal effect of radiation therapy were reviewed and the outcomes have been summarized. Currently, only clinical case reports and anecdotes have slowly converted into solid clinical data and interest is building in the field of radiation therapy, specifically on how local radiation can produce the abscopal effects for the management of different types of malignant tumors. Extensive clinical evidence suggests that the radiation therapy induced abscopal antitumor effects are mediated by immune cells such as the T-lymphocytes. This forms a basis for using radiation therapy in combination with immunotherapy to augment the abscopal response rates in cancer patients. Current evidence demonstrates that radiation therapy induces abscopal responses across many tumor types. Together, the clinical outcomes from published reports suggest that localized radiation therapy is capable of inducing abscopal effects in a wide variety of malignant tumors. With the advent of novel immunotherapies, the potential for immune activation by radiation defines a novel role for radiation therapy in the treatment of systemic disease. A clinical consideration of the abscopal effects produced by radiation therapy could lead to a revolutionary change in the current management of patients including radiation treatment strategies and immunotherapies for various malignant tumors.

The Abscopal Effect of Stereotactic Radiotherapy and Immunotherapy: Fool's Gold or El Dorado?

An ‘abscopal’ effect if often used to refer to distant tumour regression after localised irradiation. Since the first report of the abscopal effect in the 1950s, well-documented cases with radiotherapy alone are very rare. It is widely accepted that the immune response plays an important role in the abscopal effect, although the mechanism is still unclear. With the recent success of cancer immunotherapy, there is growing interest in combining immunotherapy with radiotherapy to boost abscopal response rates. Compared with conventional radiotherapy, stereotactic ablative radiotherapy (SABR) not only delivers ablative dose to the tumour, but may also induce robust immune responses. In this review we examine studies that combine SABR and immunotherapy. We review the preclinical rationale for SABR and immunotherapy combinations, the case for and against abscopal effects, and the current landscape of clinical trials.

Novel stereotactic body radiation therapy (SBRT)-based partial tumor irradiation targeting hypoxic segment of bulky tumors (SBRT-PATHY): improvement of the radiotherapy outcome by exploiting the bystander and abscopal effects

BackgroundDespite the advances in oncology, patients with bulky tumors have worse prognosis and often receive only palliative treatments. Bulky disease represents an important challenging obstacle for all currently available radical treatment options including conventional radiotherapy. The purpose of this study was to assess a retrospective outcome on the use of a newly developed unconventional stereotactic body radiation therapy (SBRT) for PArtial Tumor irradiation of unresectable bulky tumors targeting exclusively their HYpoxic segment (SBRT-PATHY) that exploits the non-targeted effects of radiotherapy: bystander effects (local) and the abscopal effects (distant).Materials and methodsTwenty-three patients with bulky tumors received partial bulky irradiation in order to induce the local non-targeted effect of radiation (bystander effect). The hypoxic tumor segment, called the bystander tumor volume (BTV), was defined using PET and contrast-enhanced CT, as a hypovascularized-hypometabolic junctional zone between the central necrotic and peripheral hypervascularized-hypermetabolic tumor segment. Based on tumor site and volume, the BTV was irradiated with 1–3 fractions of 10–12 Gy prescribed to 70% isodose-line. The pathologic lymph nodes and metastases were not irradiated in order to assess the distant non-targeted effects of radiation (abscopal effect). No patient received any systemic therapy.ResultsAt the time of analysis, with median follow-up of 9.4 months (range: 4–20), 87% of patients remained progression-free. The bystander and abscopal response rates were 96 and 52%, respectively. Median shrinkage of partially irradiated bulky tumor expressing intensity of the bystander effect was 70% (range 30–100%), whereas for the non-irradiated metastases (intensity of the abscopal effect), it was 50% (range 30–100%). No patient experienced acute or late toxicity of any grade.ConclusionsSBRT-PATHY showed very inspiring results on exploitation of the radiation-hypoxia-induced non-targeted effects that need to be confirmed through our ongoing prospective trial.Present study has been retrospectively registered by the local ethic committee under study number A 26/18.

Using immunotherapy to boost the abscopal effect.

More than 60 years ago, the effect whereby radiotherapy at one site may lead to regression of metastatic cancer at distant sites that are not irradiated was described and called the abscopal effect (from 'ab scopus', that is, away from the target). The abscopal effect has been connected to mechanisms involving the immune system. However, the effect is rare because at the time of treatment, established immune-tolerance mechanisms may hamper the development of sufficiently robust abscopal responses. Today, the growing consensus is that combining radiotherapy with immunotherapy provides an opportunity to boost abscopal response rates, extending the use of radiotherapy to treatment of both local and metastatic disease. In this Opinion article, we review evidence for this growing consensus and highlight emerging limitations to boosting the abscopal effect using immunotherapy. This is followed by a perspective on current and potential cross-disciplinary approaches, including the use of smart materials to address these limitations.

Abstract OT1-02-02: A phase II study of pembrolizumab in combination with palliative radiotherapy for metastatic hormone receptor positive breast cancer

Abstract BACKGROUND: Despite recent advances in the treatment of patients with metastatic hormone receptor positive (HR+)/HER2- breast cancer (BC), it remains an incurable disease. The activity of immune checkpoint inhibitors (ICI) as monotherapy in patients with metastatic HR+/HER2- BC has been limited. Therefore, the addition of other strategies that elicit an immunogenic tumor microenvironment may be needed. We hypothesize that radiation therapy (RT) will potentiate the efficacy of the PD-1 inhibitor pembrolizumab in patients with metastatic HR+/HER2- BC. METHODS: Trial Design: This is a phase II single arm study assessing objective response rate (ORR) according to RECIST 1.1 in patients with metastatic HR+/HER2- BC who will receive pembrolizumab in combination with palliative RT. Pembrolizumab 200 mg intravenously will be administered 2-7 days before day 1 of RT, and will be given every 21 days until disease progression. Biopsies will be performed in the same lesion at baseline (mandatory if tumor tissue is accessible outside the field of RT) and during cycle 2 within 7-14 days before the day 1 of cycle 3 of pembrolizumab. Key Eligibility Criteria: Patients with metastatic HR+/HER2- BC, with measurable disease outside the field of radiation, for whom palliative RT to at least one bone, lymph node, or soft tissue lesion is indicated. Radiation of visceral lesions (such as lung or hepatic lesions) is not permitted. Although prior RT is allowed, patients must be at least 3 months free from RT; Re-irradiation of the same field is not allowed. There is no limit to the number of previous treatments, and systemic treatment naive patients for metastatic disease are also eligible. Specific Aims: The primary aim is to evaluate the efficacy of the combination, as defined by objective response rate (ORR) outside the field of RT according to RECIST 1.1. Secondary objectives include to determine the ORR according to immune-related criteria, the progression-free survival, the abscopal response rate, the clinical benefit rate, the safety and the tolerability of the combination. In addition, correlative studies will be performed to explore the correlation of immunosuppressive and/or immune-stimulating immune marker profiles at baseline and after cycle 2 to disease response to therapy. Statistical Methods: Using the Simons “optimal” method, in the first stage, 8 patients will be enrolled. If there is at least 1 response, accrual will continue to the second stage where up to 19 additional patients will be enrolled. If at least 3 of these 27 patients have an objective response (≥10%), the regimen will be considered worthy of further study. With this design, the probability of stopping the trial early is 78% if the true response rate is 3%. If the true response rate is 20% the chance that the regimen is declared worthy of further study is 80%. Patient accrual and target accrual: The trial opened in April/2017, and so far, has accrued 2 patients with a target accrual of 27 patients. Accrual should be complete in 14-25 months. Clinical trial information: NCT03051672. Citation Format: Barroso-Sousa R, Gao H, Barry WT, Krop IE, Schoenfeld JD, Tolaney SM. A phase II study of pembrolizumab in combination with palliative radiotherapy for metastatic hormone receptor positive breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-02-02.

Abstract 2941: Local tumor irradiation combined with α-PDL-1 immune checkpoint inhibition results in local and systemic anti-tumor responses: Successful translation of a mouse model to a human case series

Abstract Introduction: Tumor irradiation induces innate and adaptive immune responses which, rarely, lead to tumor regression at distant sites, the abscopal effect. We have previously demonstrated that immunotherapy including Toll-like-receptor agonists (CpG) and checkpoint inhibitors (anti-CTLA4) both preclinically and clinically (NCT00185965 &amp; NCT01769222) can significantly increase the rate of systemic, abscopal responses (Kim, Blood 2012 &amp; Brody, JCO 2010). Here we provide the first report of a preclinical murine model and patient case series following local radiation and systemic anti-PD-L1 (NCT01375842). Methods: Preclinical modeling was performed in a two-tumor, syngenic, A20, lymphoma BALB/c model combining fractionated single tumor radiation and systemic (i.p.) anti-PD-L1. Patients receiving MPDL3280A, a human mAb containing an engineered Fc-domain, as part of the phase 1 clinical trial with mixed responses or asymptomatic progression of disease were eligible for the addition of local radiation therapy. Murine and human immune responses including cell phenotype and function, specifically assessing expression of PD-L1 and production of IFNγ were determined by standard flow cytometry and time of flight mass cytometry (CyTOF). Results: Fractionated radiation delayed tumor growth at the treated site only, and systemic anti-PD-L1 reduced tumor growth rate at both sites, however despite prolonged survival all mice died by day 38 following either monotherapy (radiation or anti-PD-L1). In contrast, combination local fractionated radiation and systemic anti-PD-L1 flattened tumor growth at both the irradiated and un-irradiated site, and prolonged survival with 50% survival at day 48 post-tumor inoculation. Modulation of PD-L1 expression post-radiation and tumor-specific augmentation of IFNγ secretion correlated with the enhanced anti-tumor activity. Five patients including four with solid tumors received fractionated, non-definitive dose radiation with at least stabilization of systemic progression in all patients and a RECIST partial response at systemic sites in 1 patient, notably with a synovial sarcoma. Transient, grade 1-2 inflammatory adverse events (fevers, flu-like symptoms) occurred with no DLTs or serious immune-related toxicities. Modulation of PD-L1 expression, T cell phenotype and IFNγ secretion was observed and updated clinical and immune response will be presented. Conclusion: We provide the first report of combination local radiotherapy with anti-PD-L1 demonstrating synergy in a preclinical model and clinical activity in a limited case series. The magnitude of the immune response and abscopal response rate in mice and humans provides proof-of-concept that anti-PD-L1 may be an equally if not more potent combination immunotherapy with radiation compared to our experience with CpG and/or anti-CTLA4. Citation Format: Idit Sagiv-Barfi, Amanda Rajapaksa, Debra Czerwinski, Serena Chang, Jonathan Hebb, Cariad Chester, Erin Waller, Gregg Fine, Daniel Chen, Marcin Kowanetz, Bryan Irving, Ronald Levy, Holbrook Kohrt. Local tumor irradiation combined with α-PDL-1 immune checkpoint inhibition results in local and systemic anti-tumor responses: Successful translation of a mouse model to a human case series. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2941. doi:10.1158/1538-7445.AM2014-2941