Rita Nigam

First-in-man application of a novel therapeutic cancer vaccine formulation with the capacity to induce multi-functional T cell responses in ovarian, breast and prostate cancer patients

BackgroundDepoVaxTM is a novel non-emulsion depot-forming vaccine platform with the capacity to significantly enhance the immunogenicity of peptide cancer antigens. Naturally processed HLA-A2 restricted peptides presented by breast, ovarian and prostate cancer cells were used as antigens to create a therapeutic cancer vaccine, DPX-0907.MethodsA phase I clinical study was designed to examine the safety and immune activating potential of DPX-0907 in advanced stage breast, ovarian and prostate cancer patients. A total of 23 late stage cancer patients were recruited and were divided into two dose/volume cohorts in a three immunization protocol.ResultsDPX-0907 was shown to be safe with injection site reactions being the most commonly reported adverse event. All breast cancer patients (3/3), most of ovarian (5/6) and one third of prostate (3/9) cancer patients exhibited detectable immune responses, resulting in a 61% immunological response rate. Immune responses were generally observed in patients with better disease control after their last prior treatment. Antigen-specific responses were detected in 73% of immune responders (44% of evaluable patients) after the first vaccination. In 83% of immune responders (50% of evaluable patients), peptide-specific T cell responses were detected at ≥2 time points post vaccination with 64% of the responders (39% of evaluable patients) showing evidence of immune persistence. Immune monitoring also demonstrated the generation of antigen-specific T cell memory with the ability to secrete multiple Type 1 cytokines.ConclusionsThe novel DepoVax formulation promotes multifunctional effector memory responses to peptide-based tumor associated antigens. The data supports the capacity of DPX-0907 to elicit Type-1 biased immune responses, warranting further clinical development of the vaccine. This study underscores the importance of applying vaccines in clinical settings in which patients are more likely to be immune competent.Trial RegistrationClinicalTrials.gov NCT01095848

Survivin-targeted immunotherapy drives robust polyfunctional T cell generation and differentiation in advanced ovarian cancer patients

DepoVax™ is an innovative and strongly immunogenic vaccine platform. Survivin is highly expressed in many tumor types and has reported prognostic value. To generate tumor-specific immune response, a novel cancer vaccine was formulated in DepoVax platform (DPX-Survivac) using survivin HLA class I peptides. Safety and immune potency of DPX-Survivac was tested in combination with immune-modulator metronomic cyclophosphamide in ovarian cancer patients. All the patients receiving the therapy produced antigen-specific immune responses; higher dose vaccine and cyclophosphamide treatment generating significantly higher magnitude responses. Strong T cell responses were associated with differentiation of naïve T cells into central/effector memory (CM/EM) and late differentiated (LD) polyfunctional antigen-specific CD4+ and CD8+ T cells. This approach enabled rapid de novo activation/expansion of vaccine antigen-specific CD8+ T cells and provided a strong rationale for further testing to determine clinical benefits associated with this immune activation. These data represent vaccine-induced T cell activation in a clinical setting to a self-tumor antigen previously described only in animal models.

Abstract B113: Translational studies demonstrate that treatment with anti-PD-1 in unresponsive tumors can be improved by enhancing T cell activation in the tumor microenvironment with vaccine based immune therapy

Checkpoint blockade using monoclonal antibodies has been a significant breakthrough for patients that are non-responsive to conventional therapy. Anti-PD-1 therapy can reactivate tumor infiltrating leukocytes (TILs) that were rendered exhausted due to suppression mediated by PD-L1-upregulation on tumor or antigen presenting cells. However if there are no pre-existing TILs, anti-PD-1 therapy is believed to be less effective. DPX-Survivac is a potent, peptide-based T cell activation therapy that contains multiple HLA class 1 restricted antigens from the oncoprotein survivin and is formulated in the DepoVaxTM platform, a unique lipid-in-oil formulation. In Phase 1/1b clinical trials, DPX-Survivac in combination with metronomic cyclophosphamide (mCPA; 50 mg BID) could enhance systemic immune responses detected by IFN-γ ELISPOT and tetramer analysis of PBMCs. We evaluated if this combination could potentially facilitate treatment of anti-PD-1 non-responsive tumors in a HPV-expressing murine tumor model (C3). Untreated C3 tumors had low expression of PD-L1 in vivo and low TILs. Anti-PD-1 treatment alone provided no protection from tumor growth. Treatment of mice bearing advanced tumors with DPX peptide vaccine and mCPA (20 mg/kg PO) increased the levels of antigen-specific CD8a+ T cells within the tumor microenvironment, detected using flow cytometry. We also detected increased expression of PD-1 on the T cells and PD-L1 on the tumor cells, suggesting that the tumor microenvironment (TME) was mediating immune suppression through increased PD-1:PD-L1 signaling. Treatment of tumor bearing mice with vaccine, mCPA and anti-PD-1 resulted in better tumor control of established tumors. Analysis of tumor infiltrating leukocytes by flow cytometry demonstrated that anti-PD-1 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 detected an increase in expression of cytotoxic T cell gene signatures within the tumor in combination with anti-PD-1 treatment. Clonal analysis was performed of the total TCRβ sequences using gDNA extracted from the tumors. Vaccine and mCPA treatment resulted in selective expansion of clones, as the top 10 clones accounted for 35% of the total TCRβ sequences; tri-therapy including anti-PD-1 significantly enhanced the expansion of T cells within the TME so that the top 10 clones accounted for 46% of the total TCRβ sequences (p Citation Format: Genevieve Weir, Olga Hrytsenko, Richard van der Jagt, Matthew Cheung, Rena Buckstein, Tara Quinton, Lisa MacDonald, Rita Nigam, Marc Mansour, Neil L. Berinstein, Marianne Stanford. Translational studies demonstrate that treatment with anti-PD-1 in unresponsive tumors can be improved by enhancing T cell activation in the tumor microenvironment with vaccine based immune therapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B113.

Abstract 5534: Evaluation of clinical safety and immunogenicity of DPX-0907, a multi-epitope vaccine for the treatment of breast, ovarian and prostate cancers

A successful cancer vaccine needs to overcome tumor-induced immune suppression while enhancing protective Type1-biased tumor-specific immune responses. To achieve this, enhanced vaccine delivery technologies are needed. We have developed a novel liposome-in-oil depot vaccine platform called DepoVaxTM (DPX) which increases the potency of peptide-based cancer vaccines and elicits a strong cytotoxic T cell response. DPX-0907 is a human DPX-based vaccine containing 7 HLA-A2 restricted peptides and is indicated for breast, ovarian and prostate cancer. The antigens were carefully selected with a multi-targeted approach that focuses on proteins involved in pathways that are critical for the survival of a cancer cell. This reduces the likelihood of immune escape through loss of antigen expression/presentation as a tumor responds to vaccine-induced immune pressure. We recently showed that DPX-0907 produces stronger and better sustained immune responses in HLA-A2 transgenic mice than a GM-CSF/ emulsion vaccine. A multicenter phase I clinical trial was initiated in five US clinical sites in March 2010 to evaluate the safety and immunogenicity of DPX-0907 in patients with advanced breast, ovarian or prostate cancer. The open label, dose escalation study recruited patients into one of 2 dose levels (0.25 mL and 1 mL). The vaccine was administered subcutaneously every three weeks for a total of three vaccinations. PBMC9s were collected prior to each vaccination and at three time points following the last vaccination. These samples were also used to monitor the immunosuppressive MDSC population in patients receiving the vaccine treatment. In addition, immune monitoring of vaccine-induced responses is based on multi-parametric intracellular cytokine staining of multiple immune cell types and the functional analysis of peptide-MHC-multimer positive CD8 T cells. This first- in-man trial has generated important safety information that support the use of DepoVax for delivering multi-peptide based vaccines. The extensive immune monitoring will aid in the rational design of future DPX-0907 and other DepoVax-based vaccine trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5534. doi:10.1158/1538-7445.AM2011-5534