Abstract B91: Anti-PD1 blockade increases the activity of tumor infiltrating antigen-specific CD8 T cells induced by a potent peptide vaccine in combination with metronomic cyclophosphamide
Bibliographic record
Abstract
Abstract Future cancer immunotherapies will combine multiple treatments to improve immune responses to cancer through synergistic, multi-modal mechanisms. In Phase 1 and 1b clinical trials, we found that metronomic cyclophosphamide (mCPA; 50 mg BID) enhanced the immunogenicity of a DepoVaxTM (DPX) based cancer vaccine (DPX-Survivac) in ovarian cancer patients. We reproduced these results in preclinical transplantable tumor models which allowed us to study the underlying mechanisms of cyclophosphamide-induced immune modulation, as well as explore additional combinations to enhance the therapeutic effect. In syngeneic murine models, mCPA on alternating weeks (20 mg/kg/day PO) in combination with DPX peptide vaccines provided long-term control of established tumors. Using a HPV-expressing tumor model (C3), we found that the combination of mCPA with vaccination caused selective enrichment of antigen-specific CD8+ T cells resulting in increased immune responses detected by IFN-γ ELISPOT and in vivo cytotoxicity assay, as well as improved protection from tumors. Efficacy of the vaccine and mCPA combination was limited in mice bearing advanced tumors. However, antigen-specific CD8+ T cells could be detected infiltrating the tumor by flow cytometry along with increased expression of PD-1 by qPCR, suggesting that the combination therapy was able to generate strong cytotoxic T cell response but was still subject to tumor induced suppression within the tumor microenvironment. Tumor bearing mice treated with vaccine, mCPA and anti-PD-1 blockade (with anti-PD1 or anti-PDL1) could control and induce regression of established tumors which could not be successfully treated with antibody monotherapy. Ex vivo analysis of tumor infiltrating cells demonstrated that anti-PD1 treatment did not further enhance tumor infiltration with antigen-specific CD8 T cells induced by the vaccine/ mCPA treatment, however, RT-qPCR analysis of the tumor demonstrated an increase in expression of cytotoxic T cell gene signatures with anti-PD1 treatment within the tumor; these results were confirmed in RT-qPCR analysis of tumor draining lymph node. An increased expression of PDL-1 was also detected in all vaccinated mice, regardless of whether they were also treated with anti-PD1. We conclude that enhanced tumor control mediated by the tri-therapy is mediated by highly active, tumor-specific cytotoxic T lymphocytes produced by a strongly immunogenic vaccine. These results provide a rationale for clinical testing of checkpoint blockade therapy in combination with our highly immunogenic combination of mCPA and DPX-Survivac. Citation Format: Genevieve Weir, Olga Hrytsenko, Marianne Stanford, Mohan Karkada, Neil Berinstein, Marc Mansour. Anti-PD1 blockade increases the activity of tumor infiltrating antigen-specific CD8 T cells induced by a potent peptide vaccine in combination with metronomic cyclophosphamide. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B91.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".