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Background Gene-modified autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) reactive against the NY-ESO-1-specific HLA-A*02-restricted peptide SLLMWITQC (NY-ESO-1 SPEAR T-cells; GSK 794), have demonstrated clinical activity in patients with advanced synovial sarcoma (SS). The factors contributing to gene-modified T-cell expansion and the changes within the tumor microenvironment (TME) following T-cell infusion remain unclear. These studies address the immunological mechanisms of response and resistance in patients with SS treated with NY-ESO-1 SPEAR T-cells. Methods Four cohorts were included to evaluate antigen expression and preconditioning on efficacy. Clinical responses were assessed by RECIST v1.1. Engineered T-cell persistence was determined by qPCR. Serum cytokines were evaluated by immunoassay. Transcriptomic analyses and immunohistochemistry were performed on tumor biopsies from patients before and after T-cell infusion. Gene-modified T-cells were detected within the TME via an RNAish assay. Results Responses across cohorts were affected by preconditioning and intra-tumoral NY-ESO-1 expression. Of the 42 patients reported (data cut-off 4June2018), 1 patient had a complete response, 14 patients had partial responses, 24 patients had stable disease, and 3 patients had progressive disease. The magnitude of gene-modified T-cell expansion shortly after infusion was associated with response in patients with high intra-tumoral NY-ESO-1 expression. Patients receiving a fludarabine-containing conditioning regimen experienced increases in serum IL-7 and IL-15. Prior to infusion, the TME exhibited minimal leukocyte infiltration; CD163+ tumor-associated macrophages (TAMs) were the dominant population. Modest increases in intra-tumoral leukocytes (≤5%) were observed in a subset of subjects at approximately 8 weeks. Beyond 8 weeks post infusion, the TME was minimally infiltrated with a TAM-dominant leukocyte infiltrate. Tumor-associated antigens and antigen presentation did not significantly change within the tumor post-T-cell infusion. Finally, NY-ESO-1 SPEAR T cells trafficked to the TME and maintained cytotoxicity in a subset of patients. Conclusions Our studies elucidate some factors that underpin response and resistance to NY-ESO-1 SPEAR T-cell therapy. From these data, we conclude that a lymphodepletion regimen containing high doses of fludarabine and cyclophosphamide is necessary for SPEAR T-cell persistence and efficacy. Furthermore, these data demonstrate that non-T-cell inflamed tumors, which are resistant to PD-1/PD-L1 inhibitors, can be treated with adoptive T-cell based immunotherapy. Trial registration ClinicalTrials.gov, NCT01343043, Registered 27 April 2011.

BackgroundAGEN1181 is a novel anti-CTLA-4 antibody with enhanced FcyR-dependent functionality, engineered to bind high and low binding alleles of FcyRIIIA, promoting superior T cell priming, memory responses, and depletion of intratumoral T regulatory cells. Further, AGEN1181 avoids complement recruitment, predictive of better tolerability. Here we report initial safety and efficacy findings from a phase I/Ib study of AGEN1181 as monotherapy and in combination with balstilimab (BAL; anti-PD-1).MethodsEligible patients (pts) had advanced solid tumors refractory to standard therapies. AGEN1181 was dosed Q3W (0.1–3 mg/kg) or Q6W (1–2 mg/kg) as monotherapy, or Q6W (0.1–2 mg/kg) in combination with BAL Q2W (3 mg/kg).ResultsAs of July 16th 2021, 102 pts received AGEN1181 (43 monotherapy, 59 combination). Median age, 63 years (29–83); 50.5% with ≥3 prior lines of therapy. MTD not yet reached with AGEN1181 dosing up to 3 mg/kg Q3W as monotherapy and 2 mg/kg in combination with BAL. The most common treatment-related adverse events (TRAEs) of any grade were fatigue (34.3%), diarrhea (32.4%), and nausea (19.6%) with grade ≥3 events in 21.6% (diarrhea/colitis, 11.8%, fatigue, 2.9%). Notably, no immune-related hypophysitis or pneumonitis has been observed. Discontinuation from AGEN1181 due to TRAEs occurred in 15% of pts. Grade 5 TRAEs occurred in two pts (colitis [chronic], intestinal perforation). The disease control rate in evaluable pts (completed ≥1 on-treatment scan) defined as best overall response of CR, PR, or SD ≥6 weeks was 48.1% for AGEN1181 monotherapy ≥1 mg/kg (1 CR, 3 PR, 9 SD) and 70% for combination (3 PR, 6 unconfirmed PR [uPR], 19 SD). Monotherapy responders include individual pts with MSS endometrial cancer (CR), PD-1-relapsed/refractory cervical cancer (PR), PD-1-relapsed/refractory melanoma (PR), and pancreatic cancer (PR). Enrollment is continuing in several disease expansion cohorts with combination therapy. For MSS CRC, 2 PR, 2 uPR, and 7 SD have been seen in 17 evaluable ≥1 mg/kg patients to date. In the ovarian cohort (n=6), 2 PRs and 3 SD are noted. Additional combination responders include one PR and uPR in MSS endometrial cancer, two uPRs in visceral angiosarcoma (uPRs) and one uPR in PD-1-relapsed/refractory NSCLC (uPR); the majority of the responses are recent and ongoing.ConclusionsAGEN1181 alone and in combination with BAL demonstrates favorable tolerability and compelling clinical activity, notably in poorly immunogenic tumor types and PD-1-refractory pts. These results underscore the significant potential of AGEN1181 to expand benefit of anti-CTLA-4 therapy to a broader patient population.Trial RegistrationNCT03860272Ethics ApprovalThe study obtained ethics approval at each participating center (UT Health Sciences Center at San Antonio, University of Colorado Cancer Center, St John’s Cancer Institute, and HonorHealth under WIRB Study number 1256391; USC Norris Comprehensive Cancer Center, Beth Israel Deaconess Medical Center, and MD Anderson Cancer Center, approval numbers HS19-00277, 19–132, and 140346, respectively). All patients provided written informed consent in accordance with federal, local, and institutional guidelines.

Angiosarcoma is an uncommon endothelial malignancy and a highly aggressive soft tissue sarcoma. Due to its infiltrative nature, successful management of localized angiosarcoma is often challenging. Systemic chemotherapy is used in the metastatic setting and occasionally in patients with high-risk localized disease in neoadjuvant or adjuvant settings. However, responses tend to be short-lived and most patients succumb to metastatic disease. Novel therapies are needed for patients with angiosarcomas.We performed a retrospective analysis of patients with locally advanced or metastatic angiosarcoma, who were treated with checkpoint inhibitors at our institution. We collected their clinical information and outcome measurements. In one patient with achieved complete response, we analyzed circulating and infiltrating T cells within peripheral blood and tumor tissue.We have treated seven angiosarcoma (AS) patients with checkpoint inhibitors either in the context of clinical trials or off label [Pembrolizumab + Axitinib (NCT02636725; n = 1), AGEN1884, a CTLA-4 inhibitor (NCT02694822; n = 2), Pembrolizumab (n = 4)]. Five patients had cutaneous angiosarcoma, one primary breast angiosarcoma and one radiation-associated breast angiosarcoma. At 12 weeks, 5/7 patients (71%) had partial response of their lesions either on imaging and/or clinical exam and two (29%) had progressive disease. 6/7 patients are alive to date and, thus far, 3/7 patients (43%) have progressed (median 3.4 months)- one achieved partial response after pembrolizumab was switched to ongoing Nivolumab/Ipilimumab, one died of progressive disease at 31 weeks (primary breast angiosarcoma) and one was placed on pazopanib. One patient had a complete response (CR) following extended treatment with monotherapy AGEN1884. No patient experienced any ≥ grade 2 toxicities.This case series underscores the value of targeted immunotherapy in treating angiosarcoma. It also identifies genetic heterogeneity of cutaneous angiosarcomas and discusses specific genetic findings that may explain reported benefits from immunotherapy.

Background Angiosarcoma is an uncommon endothelial malignancy and a highly aggressive soft tissue sarcoma. Due to its infiltrative nature, successful management of localized angiosarcoma is often challenging. Systemic chemotherapy is used in the metastatic setting and occasionally in patients with high-risk localized disease in neoadjuvant or adjuvant settings. However, responses tend to be short-lived and most patients succumb to metastatic disease. Novel therapies are needed for patients with angiosarcomas. Methods We performed a retrospective analysis of patients with locally advanced or metastatic angiosarcoma, who were treated with checkpoint inhibitors at our institution. We collected their clinical information and outcome measurements. In one patient with achieved complete response, we analyzed circulating and infiltrating T cells within peripheral blood and tumor tissue. Results We have treated seven angiosarcoma (AS) patients with checkpoint inhibitors either in the context of clinical trials or off label [Pembrolizumab + Axitinib (NCT02636725; n = 1), AGEN1884, a CTLA-4 inhibitor (NCT02694822; n = 2), Pembrolizumab (n = 4)]. Five patients had cutaneous angiosarcoma, one primary breast angiosarcoma and one radiation-associated breast angiosarcoma. At 12 weeks, 5/7 patients (71%) had partial response of their lesions either on imaging and/or clinical exam and two (29%) had progressive disease. 6/7 patients are alive to date and, thus far, 3/7 patients (43%) have progressed (median 3.4 months)- one achieved partial response after pembrolizumab was switched to ongoing Nivolumab/Ipilimumab, one died of progressive disease at 31 weeks (primary breast angiosarcoma) and one was placed on pazopanib. One patient had a complete response (CR) following extended treatment with monotherapy AGEN1884. No patient experienced any ≥ grade 2 toxicities. Conclusions This case series underscores the value of targeted immunotherapy in treating angiosarcoma. It also identifies genetic heterogeneity of cutaneous angiosarcomas and discusses specific genetic findings that may explain reported benefits from immunotherapy.