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11500 Background: Ewing Sarcoma (ES) is a rare cancer of the young with very few treatment options in the relapsed/refractory (R/R) setting. Fusions of the EWS gene and one of five different ETS transcription factors are dominant drivers of ES. TK216 was designed to bind ETS proteins directly, disrupt protein-protein interactions, and inhibit transcription factor function. TK216 plus vincristine (VCR) exerted synergistic activity in non-clinical models . Here, we report updated interim results of the Phase 1/2 trial of TK216 ± vincristine in R/R ES. Methods: TK216 was administered by continuous IV infusion to adult and pediatric patients (pts) with R/R ES using a 3+3 design. Dosing duration of 7 days was later extended to 10 and 14 days. Dose limiting toxicity was evaluated during Cycle 1. VCR could be added after Cycle 2. The MTD for the 14-day infusion was 200 mg/m2/d, which was selected as the recommended Phase 2 dose (RP2D) for the Expansion cohort, with VCR started in Cycle 1. Results: Thirty-two R/R pts in 9 dose and schedule escalation cohorts, and 31 pts in the Phase 2 Expansion cohort were enrolled. Thirty-five pts were treated at the RP2D. Mean age was 30.6 years and 61% were males. Median prior treatment regimens for recurrent/metastatic ES were 3 (range 0-13). Median time from initial diagnosis of ES to study start was 3.5 years (range 0.3-18.1). Prior procedures included surgery (84%) and radiation (81%). At study entry, all pts had metastases with sites being bone only (13%), pleuropulmonary only (39%), and other metastatic (47%). As of the 20JAN2021 safety cutoff, the most common AEs observed in 62 treated pts, regardless of causality, included anemia (n = 34), neutropenia (n = 30) and fatigue (n = 25). Myelosuppression observed was transient, reversible, and responsive to growth factors. No deaths were attributed to TK216. As of the 06FEB2021 efficacy cut-off, 28/35 pts treated at the RP2D were evaluable for efficacy: Complete response (CR) 7.1%, stable disease (SD) 39.3%, progressive disease (PD) 53.6%, for an overall clinical benefit (CR+PR+SD) rate of 46.4%. SD median duration was 113 days (range 62-213). Three tumor responses were notable. One pt had regression of the target lesion after 2 cycles of TK216 alone, then after 6 cycles of TK216 + VCR therapy a residual non-target lesion was removed, for a surgical CR, without PD at 24 months on study. A second pt had a CR after 6 cycles of combination therapy, without PD at 18 months on study. After 4 cycles of TK216 + VCR therapy, a third pt had a PR of the target lesion, is receiving local therapy for PD of a non-target lesion and remains on study. Pts treated with the RP2D had a longer PFS than those in the dose escalation cohorts. Conclusions: TK216 plus VCR was well tolerated and showed encouraging early evidence of anti-tumor activity in this heavily pre-treated/ high tumor burden ES pt population. Clinical trial information: NCT02657005.

The dramatic clinical benefit of immune checkpoint blockade for a fraction of cancer patients suggests the potential for further clinical benefit in a broader cancer patient population by combining immune checkpoint inhibitors with active immunotherapies. The anti-tumor efficacy of MVA-BN-HER2 poxvirus-based active immunotherapy alone or in combination with CTLA-4 checkpoint blockade was investigated in a therapeutic CT26-HER-2 lung metastasis mouse model. MVA-BN-HER2 immunotherapy significantly improved the median overall survival compared to untreated controls or CTLA-4 blockade alone (p

Treatment with poxvirus-based active immunotherapies shows evidence of robust immune responses against a variety of tumor-associated antigens in preclinical and clinical studies. Poxvirus-based immunotherapies in development include PSA-targeted PROSTVAC, now in Phase 3 clinical development; CV-301 (targeting CEA and MUC-1); as well as MVA-BN-HER2 and MVA-BN-Brachyury (targeting HER-2 and the transcription factor Brachyury, respectively). Evidence of robust and productive anti-tumor efficacy in preclinical models was accompanied by treatment-emergent infiltration of tumors by activated cytotoxic CD8 T cells producing high amounts of IFNγ. Treatment with immune checkpoint inhibitors such as anti-PD-1 antibodies is showing significant clinical benefit by re-activating dormant tumor-specific T cells. Furthermore, preclinical studies have shown further synergistic efficacy by combining PD-1 blockade with inhibition of LAG-3, which acts independently of PD-1 to modulate T cell function. We hypothesized that poxvirus-based active immunotherapy may provide even greater improvements to patient outcome when used in combination with immune checkpoint blockade, by inducing new productive tumor-specific responses. This may be especially important in patients lacking an endogenous T cell response against their tumors. In therapeutic CT26-HER2 solid and metastatic tumor models, mice were administered MVA-BN-HER2 immunotherapy alone or in combination with anti-PD-1 and/or anti-LAG-3 antibodies. Synergistic benefit for anti-tumor efficacy was observed when combining MVA-BN-HER2 immunotherapy with anti-PD-1 alone, while combination with anti-LAG-3 alone had little effect. Notably, a further enhancement occurred when MVA-BN-HER2 immunotherapy was combined with PD-1 and LAG-3 blockade as shown by complete tumor regression in 20/20 mice. Subsequent rejection of HER-2 negative tumors 6 months after the original challenge revealed that immune responses were durable and included antigen spread to additional tumor antigens. Flow cytometric analysis demonstrated that tumor infiltrating lymphocytes (TILs) in untreated tumors were PD-1hi and LAG-3+, a more exhausted phenotype. Poxvirus-based immunotherapy led to the induction of activated TILs characterized by low to mid-levels of PD-1 expression. While PD-1 blockade prevented binding to PD-L1 it also caused an increase in LAG-3 expression on T cells. Together these data provide further rationale for why combination therapy of poxvirus-based immunotherapy with inhibition of PD-1 plus LAG-3 resulted in synergistic efficacy in preclinical tumor models. Overall these data demonstrate that combining complementary immune-based therapies such as poxvirus-based active immunotherapy and PD-1 plus LAG-3 immune checkpoint blockade result in synergistic anti-tumor efficacy. Citation Format: Barbara Sennino, Susan P. Foy, Ryan B. Rountree, Tracy dela Cruz, Evan J. Gordon, Veronica Xavier, Felicia Kemp, Alex Franzusoff, James Breitmeyer, Stefanie J. Mandl. Poxvirus-based active immunotherapy synergizes with PD-1 plus LAG-3 immune checkpoint inhibition to enhance antitumor efficacy in preclinical models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-234. doi:10.1158/1538-7445.AM2015-LB-234

TPS5081 Background: PROSTVAC, a targeted active immunotherapy, is being studied in men with asymptomatic to minimally symptomatic mCRPC in PROSPECT, a global double-blind, randomized phase 3 study....

3058 Background: PROSTVAC PSA-targeted immunotherapy for metastatic castration-resistant prostate cancer is being tested in the PROSPECT phase 3 trial. Another poxvirus-based immunotherapy product,...

3080 Background: PROSTVAC is being tested for treatment of metastatic castration-resistant prostate cancer in the PROSPECT phase 3 trial. PROSTVAC immunotherapy comprises subcutaneous dosing in a h...