Immune Checkpoint Inhibition With Radiation Therapy Causes an Abscopal Treatment Effect for Castrate-Resistant Prostate Cancer

TPS470 Background: Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the surface of activated T lymphocytes and causes inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. MEDI4736 is a human monoclonal antibody directed against PD-L1. Blockage of ligation between PD-L1 and PD1 induces local immune activation and prevents anergy and exhaustion of effector T-cells. Several studies have documented an increase in peripheral antitumor immunity following radiation. This effect is evidently too weak to be clinically relevant, but has the potential to be boosted by immune modulation. The underlying hypothesis of this study is that the effect of immune checkpoint inhibition (accomplished via tremelimumab and/or MEDI4736) treatment can be enhanced by radiation in patients with advanced pancreatic carcinoma. Whilst radiation treatment in pancreas cancer is commonly employed in limited or early stage disease, if radiation can enhance the effect of immune checkpoint inhibition to produce systemic anti-tumor effects the combination could become an effective treatment modality for patients with advanced disease. Methods: Patients with histologically confirmed metastatic pancreatic cancer with primary in-situ (or locally-recurrent) disease are being enrolled to this pilot study. The primary objectives are to determine the safety, tolerability and feasibility of immune checkpoint inhibition [comprising either MEDI4736 alone (Cohort A), Tremelimumab (Cohort B) or combined MEDI4736 and Tremelimumab (Cohort C)] in combination with stereotactic body radiation therapy (SBRT) in patients with unresectable pancreatic cancer. Select eligibility criteria are as follows: at least 1 measurable metastatic lesion by RECIST 1.1 criteria and accessible for biopsy. No prior radiation therapy to the pancreas allowed. There is no limit to the number of prior chemotherapy regimens received; ECOG ≤ 1; Life expectancy of greater than 3 months. Acceptable organ and bone marrow function. No active or prior documented autoimmune or inflammatory disorders. Clinical trial information: NCT02311361.

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A pilot study of immune checkpoint inhibition in combination with radiation therapy in patients with metastatic pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e15786 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e15786-e15786 ◽

Cited By ~ 4

Author(s):

Austin G. Duffy ◽

Oxana V. Makarova-Rusher ◽

David E Kleiner ◽

Christine Alewine ◽

William Douglas Figg ◽

...

Keyword(s):

Pancreatic Cancer ◽

Monoclonal Antibody ◽

Radiation Therapy ◽

Pilot Study ◽

Immune Checkpoint ◽

Advanced Pancreatic Cancer ◽

Primary Objective ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition ◽

Eligibility Criteria

e15786 Background: Durvalumab is a human IgG1 monoclonal antibody directed against PD-L1. Tremelimumab is a selective human IgG2 monoclonal antibody against CTLA-4. Several studies have documented an increase in peripheral antitumor immunity following radiation. The hypothesis of this study is that the effect of immune checkpoint inhibition (ICI) can be enhanced by radiation in pancreatic adenocarcinoma (PAC). Methods: Patients with histologically confirmed metastatic PC with primary in-situ or metastatic SBRT-amenable disease are being enrolled to this pilot study. Primary objective to determine safety, tolerability and feasibility of immune checkpoint inhibition [comprising either Durvalumab alone (Cohort A), or combined durvalumab and tremelimumab (Cohort B)] in combination with stereotactic body radiation therapy (SBRT) at two different schedules (8Gy/single fraction or 25Gy in 5 fractions). Select eligibility criteria are as follows: at least 1 measurable metastatic lesion by RECIST 1.1 accessible for biopsy. No limit to the number of prior chemotherapy regimens; ECOG ≤ 1; Life expectancy of greater than 3 months. Acceptable organ and bone marrow function. No active autoimmune disorders. Results: N = 24 patients with chemorefractory metastatic PC have so far been enrolled; M/F = 13/11; Median age = 61. Treatment was well tolerated. No DLT encountered. The most common toxicity was fatigue (G1/2) in all patients in DL2. 5/24 pts had early discontinuation ( < 4 wks) due to rapid PD. No objective responses have been seen. 5 pts (21%) had SD as best response. Conclusions: Immune checkpoint inhibition in combination with SBRT in advanced pancreatic cancer is safe and feasible. Preliminarily no objective responses have been seen for these schedules of SBRT with durvalumab. The study is continuing with evaluation of SBRT with dual checkpoint inhibition (durvalumab and tremelimumab). Clinical trial information: NCT02311361.

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Prevalence of microsatellite instability and monitoring response to immune checkpoint inhibition utilizing liquid biopsy among African American men with advanced prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.16 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 16-16

Author(s):

Tamer Khashab ◽

Alexander D Le ◽

Samantha Cohen ◽

Salma Kaochar ◽

Heidi Dowst ◽

...

Keyword(s):

Prostate Cancer ◽

African American ◽

Microsatellite Instability ◽

Immune Checkpoint ◽

Liquid Biopsy ◽

Patient Population ◽

Safety Net ◽

Inactive Disease ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition

16 Background: African American (AA) men have higher prostate cancer (PC) incidence and PC-specific mortality than non-AA men. Socioeconomic/healthcare access and environmental factors contribute to the disparity in clinical outcomes. Moreover, AA PC exhibits increased inflammatory and immune response signaling, which may contribute to its aggressive behavior, but also allow for therapeutic intervention. Microsatellite instability (MSI) is a tissue-agnostic biomarker predictive of response to immune-checkpoint inhibition (pembrolizumab) that can be assessed by NGS testing of tumor tissue or circulating tumor DNA (ctDNA, liquid biopsy). The latter is particularly relevant for patients with PC, a disease which frequently metastasizes to bone and other deep sites, making conventional tissue biopsies invasive, painful and potentially risky. Methods: We retrospectively analyzed NGS results obtained via Tempus|xT tissue assay and/or Tempus|xF liquid biopsy assay for MSI, as well as clinical data (response to pembrolizumab), from 100 PC patients (53 AA) receiving androgen deprivation therapy for locally advanced, biochemically recurrent or metastatic disease at Ben Taub Hospital (BTH, a safety net hospital in Houston serving a patient population of which 91% are racial/ethnic minorities). We also analyzed de-identified NGS data from a nationwide cohort of 2090 metastatic PC patients (225 AA) previously sequenced with xT and/or xF by Tempus Labs (Chicago, IL). Results: MSI-High status (MSI-H) was detected using xT and/or xF assays in 4/100 (4%) of patients in the BTH cohort and in 62/2090 (3%) of metastatic PC patients in the nationwide Tempus Labs cohort. Specifically, within the AA PC patient population, MSI-H was detected in 2/53 (3.7%) in the BTH cohort and in 8/225 (3.6%) in the nationwide Tempus Labs cohort. For those patients who had both tissue and liquid biopsy testing, there was 100% concordance in MSI-H detection between the two assays. Genomically-driven treatment of two MSI-H AA CRPC patients with pembrolizumab resulted in prompt and durable clinical, biochemical and molecular responses, with precipitous decline in PSA levels to below detection limit, complete radiographic response of metastatic lymphadenopathy, radiographic non-progression of visceral disease (per iRECIST and PC Working Group 3 criteria) and disappearance of PC-derived ctDNA mutations in the liquid biopsy. Conclusions: MSI-H status is present in advanced AA PC at a frequency comparable to non-AA PC. Liquid biopsy (xF assay) is a minimally invasive tool that allows detection of MSI-H in PC patients, as well as longitudinal monitoring of response to treatment with pembrolizumab. Liquid biopsy conversion from positive to negative may provide reassurance that any residual lesions seen on imaging represent treated/inactive disease.

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