Analysis of B and T cell responses in non-small cell lung cancer (NSCLC) patients enrolled in a phase II trial of cyclophosphamide with allogenic DRibble vaccine (DPV-001
Background: Intratumoral electroporation of plasmid IL-12 (IT-pIL12-EP) induces tumor infiltrating lymphocytes (TILs) and anti-tumor immunity in melanoma as described in previous Phase 1 and 2 clinical trials. PD-1 and PD-L1 antibodies induce durable tumor responses in advanced melanoma, however responses to these agents are far less common in tumors lacking significant numbers of TILs. Therefore, in this retrospective study, patients were evaluated for response to anti-PD-1/PD-L1 therapies post IT-pIL12-EP. Methods: A multi-center, Phase 2 trial of IT-pIL12-EP was conducted in patients with stage III/IV melanoma. Upon disease progression or treatment discontinuation with IT-pIL12-EP, many patients received subsequent PD-1/PD-L1 inhibitors. Patients with documented follow up history and evaluable for anti-PD-1/PD-L1 response were included in this analysis. Results: We evaluated 34 patients enrolled and treated with IT-pIL12-EP monotherapy at a single center, of which, 14 patients went on to receive a systemic PD-1/PD-L1 inhibitor and were evaluable for PD-1/PD-L1 best overall response (BOR). The PD-1/PD-L1-associated BOR was 9/14 (64%) with CR in 5 patients (36%), PR in 4 (29%), SD in 2 (14%), and PD in 3 (21%). Eight of these evaluable patients received a systemic PD-1/PD-L1 inhibitor with no intervening therapy post-IT-pIL12-EP. Of these 8 patients, a BOR of 75% was observed (50% CR and 25% PR). Conclusion: Patients who received IT-pIL12-EP and later went on to receive a PD-1/PD-L1 inhibitor demonstrated a high PD-1/PD-L1-associated response rate (64% CR+PR). Interestingly, patients who received a PD-1/PD-L1 inhibitor with no intervening therapy post-IT-pIL12-EP had a BOR of 75% (CR+PR). These data suggest that IT-pIL12-EP may prime for responses to PD-1 blockade. Patient tumor samples are being evaluated for TIL status and gene expression analysis to determine the mechanism of IT-pIL12-EP priming. A prospective clinical trial combining IT-pIL12-EP and pembrolizumab in advanced melanoma is ongoing at the University of California San Francisco. NCT01502293 Citation Format: Alain Algazi, Katy K. Tsai, Kathryn T. Takamura, Lawrence Chen, Chris Twitty, Mary Dwyer, Samantha Greaney, Tu Diep, Robert H. Pierce, Mai H. Le, Lawrence Fong, Adil Daud. Intratumoral electroporation of plasmid IL-12 can prime response to anti-PD1/PD-L1 blockade in patients with Stage III/IV-M1a melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT134.
78 Background: Recent publications support the emergence of predictive biomarkers for pembrolizomab in melanoma based on the expression of PD-L1 in the tumor microenvironment (Daud 2016a) or the frequency of PD-1hiCTLA-4hi on CD8+ TIL (Daud 2016b) whereby immunologically inactive tumors show poor response to immune checkpoint inhibition alone. Since intratumoral pIL-12 with electroporation (IT-pIL12-EP) increases TIL in both treated and untreated lesions, we hypothesize that non-response can be rescued with the combination of IT-pIL12-EP and anti-PD-1. Phase II clinical and immunological data are shown. Methods: Melanoma stage III/IV patients were enrolled with CD8+ TIL < 25% PD-1hiCTLA-4+measured by flow cytometry (NCT02493361). PD-L1 IHC (22C3 Ab) was also evaluated. Patients were treated with pembrolizumab (200mg every 3 weeks) and IT-pIL12-EP. Patients were evaluated for ORR every 12 weeks (RECISTv1.1). Pre- and post-treatment blood and tumor specimens were collected, and analyzed for immune phenotyping, gene expression, T cell receptor diversity, and changes in the tumor microenvironment by IHC. Results: TIL assessment for evaluable enrolled patients were < 22% PD-1hiCTLA-4+, a value associated with anti-PD-1 non-response (Daud 2016b). Remarkably, although predicted to be an unresponsive population, the ORR was 40% (4CR/ 2PR) by RECISTv1.1. In patients with CR/PR, analysis of the tumor microenvironment revealed many significant immunological changes not seen in non-responders, including number and ratios of CD8+:PD-L1+by IHC, increased expression of NK, CD8 and ‘adaptive resistance’ markers by NanoString, as well as increased clonality and T cells by TCR sequencing. Conclusions: The excellent safety profile and striking 40% clinical response rate is encouraging as treated patients were predicted to be non-responsive to pembrolizumab. The correlative data shows an immune-directed mechanism that is differentiated between responders and non-responders suggesting the combination can effectively alter the tumor microenviroment to benefit patients otherwise unlikely to respond to anti-PD-1 monotherapy. Clinical trial information: NCT02493361.
Vaccination with MCA sarcoma cells protects from a subsequent challenge with the same, but not other MCA sarcomas. This observation of unique tumor-specific protection is a well-established paradigm (Prehn and Main 1957). We postulated that all MCA sarcomas overexpress common mutated gene products with a short half-life (SLiPs), but only the unique tumor-rejection antigens are stable enough to be cross-presented and induce anti-tumor immunity. We recently reported that with proteosomal blockade, SLiPs could be isolated in autophagic-containing (LC-3) vesicles (termed DRibble) that were efficient for cross-presentation of antigens (Li, Y. et al). Here we examined if vaccination with DRibbles from one MCA sarcoma would cross-protect from a challenge with an antigenically distinct MCA sarcoma. While whole tumor cell vaccines provide protection to unrelated tumor in 0 of 9 comparisons, DRibble vaccines provided significant (p<0.05) protection for 8 of 9 tumors (n=10-25 mice/group). Using a model system we showed that SLiPs play a critical role in providing antigen to DRibbles and that siRNA knock down of p62 reduced SLiPs and the capacity of DRibble to stimulate T cells. These results have shaped a model where polyubiquitinated SLiPs spared degradation by the proteasome, are picked up by p62 and delivered to autophagic vesicles. Used as a vaccine, these vesicles can cross-present neo-antigens capable of inducing cross-protection of chemically induced sarcomas. Supported by CA80964 (BAF), CA107243 (HH) the Chiles Foundation and the Murdoch Trust.
Interleukin-12 (IL-12) is a pro-inflammatory cytokine involved in the generation of an inflammatory tumor microenvironment and is critical in eliciting a productive anti-tumor immune response. It has been investigated as an anti-cancer therapeutic using various delivery routes, but intratumoral injection of plasmid IL-12 (tavokinogene telseplasmid; TAVO) followed by electroporation is a gene therapy approach that results in more sustained production of IL-12 locally with minimal systemic immune-related toxicity. Here we show that TAVO not only provides protection in the treated triple-negative breast cancer (TNBC) lesion, but also induces a systemic, abscopal effect. Single cell RNAsequencing (scRNAseq) of infiltrating immune cells shows a significant increase in both CD4 and CD8 T cells as well as dendritic cells within the treated lesions, while simultaneously decreasing a granulocytic myeloid derived suppressor population. scRNAseq allows for a detailed look into not only the overall pathway enrichment caused by TAVO treatment, but also the specific receptor-ligand interactions occurring between cell types. A combination of these analyses revealed an enrichment in the IFN-gamma induced PDL1 pathway by TAVO, typified by an increase in the interaction between PDL1 on dendritic cells and PD1 on CD8 T cells. Further, dramatic enrichment of the CXCL9/10/11/CXCR3 axis was observed, consistent with previous studies in melanoma. Analysis of paired TCR alpha and beta chains on T cells additionally demonstrated a dramatic shift in tumor infiltrating T cell (TIL) clonality and frequency. In sum, these preclinical studies identify a signature of increased antigen presentation, T cell infiltration and expansion, and a decrease in the number of granulocytes but also a particular enhancement of the PDL1 immunosuppressive pathway following TAVO treatment. Using this signature, we focus on an in-depth analysis of 2 patients from a single arm, prospective clinical trial of TAVO monotherapy (OMS-I140) in pre-treated advanced TNBC that went on to receive anti-PD-1 as their immediate next therapy with clinical anti-tumor response. Together these data support the combination of TAVO with PD1/PDL1 inhibitors while also identifying other key pathways that may enhance responsiveness in TNBC patients for whom treatment options remain limited. Citation Format: Erika J Crosby, Hiroshi Nagata, Melinda L Telli, Chaitanya R Acharya, Irene Wapnir, Kaitlin Zablotsky, Erica Browning, Reneta Hermiz, Lauren Svenson, Donna Bannavong, Kellie Malloy, David A Canton, Chris G Twitty, Takuya Osada, Herbert Kim Lyerly. Intratumoral delivery of tavokinogene telseplasmid (plasmid IL-12) and electroporation induces an immune signature that predicts successful combination in patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-22.
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