Elucidating immunologic mechanisms of PROSTVAC cancer immunotherapy "Beyond the Abstract," by Stefanie Mandl, PhD

BERKELEY, CA (UroToday.com) - Recently, cancer therapy is being revolutionized by the emergence of immunotherapies such as therapeutic cancer vaccines and immune checkpoint inhibitors. PROSTVAC® is a poxvirus-based, prostate-specific antigen (PSA)-targeted active immunotherapy under investigation for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Poxvirus-based active immunotherapies have been optimized over the last 20 years to induce a robust and targeted T cell immune response over time, hence assisting the patient’s own immune system to recognize and kill the cancer. In a multicenter, randomized, phase 2 study, PROSTVAC was generally well tolerated and prolonged median overall survival (mOS) by 8.5 months in men with mCRPC compared with those who received placebo (Figure 1, 25.1 vs 16.6 months, respectively; P=0.006, HR=0.56) and reduced the death rate by 44%.[1] This is the most pronounced survival benefit to date for the treatment of mCRPC. By comparison, the clinical studies supporting FDA approval of the immunotherapy Provenge for mCRPC improved the median overall survival by 4.1 months.[2] Abiraterone acetate (Zytiga®) and enzalutamide (Xtandi®), two androgen ablation therapies, extended survival by 4.6 and 2.2 months, respectively, in chemotherapy-naïve men with mCPRC.[3, 4] An international, randomized, placebo-controlled Phase 3 study (PROSPECT; NCT01322490) for PROSTVAC is currently underway to validate the observed survival benefit of the Phase 2 study in men with asymptomatic or minimally symptomatic mCRPC. Target enrollment of 1 200 patients for the PROSPECT trial has recently been reached, demonstrating the continued patient interest to engage the immune system for the treatment of prostate cancer.

PROSTVAC immunotherapy consists of a unique, heterologous, prime/boost regimen that is easily administered subcutaneously. The vaccinia-based PROSTVAC-Prime is followed by six fowlpox-based PROSTVAC-Boost doses. Both PROSTVAC-V and PROSTVAC-F contain transgenes for human PSA and 3 co-stimulatory molecules for T cells (B7.1, ICAM-1, and LFA-3, designated as TRICOM).[5] The expression of TRICOM in conjunction with the targeted antigen (PSA) has shown to result in synergistically enhanced T cell activation and anticancer efficacy.

We have made significant strides in understanding the proposed mechanism of action for PROSTVAC from analysis of immune responses in the peripheral blood of patients from several Phase 1 and 2 studies.[6, 7] These findings have been highlighted in a recent “Beyond the Abstract” article and showed that the majority of subjects tested (57%) mounted a treatment-emergent, PSA-specific T-cell response. Furthermore, 68% of patients developed novel immune responses against target-antigens personal to their own tumor, expanding the anti-cancer immune repertoire beyond the initial PSA target (a phenomenon called antigen-spread). Last but not least, T-regulatory cells were decreased in number and suppressive functionality following PROSTVAC therapy. These findings stemming from human peripheral blood suggest that PROSTVAC activates a T cell dominant immune response, but the absence of available tumor tissue made it impossible to examine the most relevant immune responses: those deployed within the tumors. Our recently published data from preclinical studies have provided new insights about how PROSTVAC may be activating productive immunity against prostate cancer. The use of animal models allowed us to investigate the mechanism of action of the observed anti-tumor activity more deeply by examination of tumor-infiltrating lymphocytes.

Some of the key new findings from these preclinical studies reflect the understanding of the magnitude and type of T-cell responses activated in response to PROSTVAC immunotherapy. First, the heterologous prime/boost regimen focuses the induced T-cell response towards the expressed tumor-associated antigen (PSA), significantly enhancing the magnitude and quality of activated PSA-specific CD4 and CD8 T cell responses. PROSTVAC-activated CD4 and CD8 T cells are highly functional and specialized effector cells, as evidenced by expression of memory T cell activation markers, production of multiple cytokines (particularly IFNγ and TNFα), and amplified cytotoxic T cell activity. Second, the observed significant anti-tumor efficacy against PSA-expressing tumors in non-clinical studies was characterized by three important processes:

  • Tumor infiltration by PROSTVAC-induced, highly activated CD8 and CD4 effector T cells.
  • Long-lasting antigen-spread immune responses that expanded the T cell repertoire from PSA to other cancer antigens and protected from challenge with non-PSA expressing tumors.
  • A greatly increased ratio of effector T cells to suppressive regulatory T cells providing the basis for a productive immune response within the normally suppressive tumor microenvironment.

These findings complement the preliminary evidence of treatment-emergent PSA-specific T cells, antigen-spread, and reduced activity of regulatory T cells observed in the peripheral blood of PROSTVAC-treated patients.

While active cancer immunotherapies show evidence for meaningful prolonged survival when given as monotherapies, immunotherapies administered in combination with other immune modulating agents are hypothesized to confer synergy of improved therapeutic benefit over any single agent, without significant intensification of the tolerability profile. Initial clinical studies combining PROSTVAC immunotherapy with anti-androgen or radiation therapies, either concomitantly or sequentially, have shown potential for therapeutic synergies with these treatment combinations.[8] PROSTVAC is currently being evaluated in combination with enzalutamide in both metastatic and non-metastatic prostate cancer (NCT01867333 and NCT01875250).

 bta mandl fig1
Figure 1: PROSTVAC + Ipilimumab: Potential for Synergistic- Impact on Median Overall Survival

Furthermore, combining PROSTVAC, which activates tumor antigen-specific T cell immune responses, with immune checkpoint inhibitors, which seek to reverse or prevent the shut-down of anti-cancer responses, is a promising direction for enhancing clinical outcomes. Pre-clinical studies demonstrated therapeutic synergy when combining PROSTVAC with immune-checkpoint inhibitors.[9] Evidence for the potential clinical benefit from combination immunotherapy was obtained in a Phase 1 dose-escalation trial. mCRPC patients were treated with a fixed dose of PROSTVAC plus escalating doses of the immune-checkpoint inhibitor Iipilimumab (Ipi, anti-CTLA4).[10] The mOS of 31.6 months from the combined cohorts was notably longer than the mOS of mCRPC patients from the randomized Phase 2 study of PROSTVAC, in which PROSTVAC immunotherapy resulted in a mOS of 25.1 months (Figure 1). Furthermore, approximately 20% of patients at 10 mg/kg (the highest Ipi dose tested) remain alive at 80 months.

Importantly, immune-related adverse events commonly associated with immune checkpoint inhibition were not exacerbated by combination with PROSTVAC immunotherapy. The potential for therapeutic synergy leading to improved survival benefit from the combination of PROSTVAC plus Ipilimumab, without significant intensification of the tolerability profile, deserves to be validated in a randomized study.

If the PROSPECT phase 3 study confirms the risk-benefit profile of PROSTVAC, this subcutaneously administered, well-tolerated, active immunotherapy has the potential to become the foundation for sequential or combination treatment for current and future prostate cancer therapies.

References:

  1. Kantoff PW, Schuetz TJ, Blumenstein BA, Glode LM, Bilhartz DL, Wyand M, Manson K, Panicali DL, Laus R, Schlom J, et al: Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol 2010, 28:1099-1105.
  2. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, et al: Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010, 363:411-422.
  3. Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, Staffurth JN, North S, Vogelzang NJ, Saad F, et al: Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. The Lancet Oncology 2012, 13:983-992.
  4. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, et al: Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014, 371:424-433.
  5. Madan RA, Arlen PM, Mohebtash M, Hodge JW, Gulley JL: Prostvac-VF: a vector-based vaccine targeting PSA in prostate cancer. Expert Opin Investig Drugs 2009, 18:1001-1011.
  6. Gulley JL, Madan RA, Tsang KY, Jochems C, Marte JL, Farsaci B, Tucker JA, Hodge JW, Liewehr DJ, Steinberg SM, et al: Immune Impact Induced by PROSTVAC (PSA-TRICOM), a Therapeutic Vaccine for Prostate Cancer. Cancer Immunology Research 2014, 2:133-141.
  7. Gulley JL, Arlen PM, Madan RA, Tsang KY, Pazdur MP, Skarupa L, Jones JL, Poole DJ, Higgins JP, Hodge JW, et al: Immunologic and prognostic factors associated with overall survival employing a poxviral-based PSA vaccine in metastatic castrate-resistant prostate cancer. Cancer Immunol Immunother 2010, 59:663-674.
  8. Shore ND: PROSTVAC(R) targeted immunotherapy candidate for prostate cancer. Immunotherapy 2014, 6:235-247.
  9. Foy SP, Mandl SJ, dela Cruz T, Cote JJ, Gordon EJ, Trent T, Franzusoff AJ, Rountree RB: Magnitude and Quality of Tumor-infiltrating T-cell response upon poxvirus-based active immunotherapy alone and in combination with CTLA-4 immune checkpoint inhibition. J Clin Oncol 2014, 32:suppl; abstr 3013.
  10. Madan RA, Mohebtash M, Arlen PM, Vergati M, Rauckhorst M, Steinberg SM, Tsang KY, Poole DJ, Parnes HL, Wright JJ, et al: Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. The Lancet Oncology 2012, 13:501-508.

Written by:
Stefanie Mandl, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

Director, Preclinical Research, Bavarian Nordic, Inc., Mountain View, CA USA

Elucidating immunologic mechanisms of PROSTVAC cancer immunotherapy - Abstract

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