Promising immunotherapies for advanced prostate cancer: playing catch-up?
Prostate cancer (PCa) is the second leading cause of cancer deaths in the USA and was the first metastatic cancer to receive Food and Drug Administration (FDA) approval for an immunotherapy: sipuleucel-T in 2010. Since that approval, immunotherapeutic progress in advanced PCa has been very limited, with only pembrolizumab, an immune checkpoint inhibitor, approved in May 2017.
PCa growth results not only from cellular neoplastic transformation but also from resistance to or escape from host defenses, which thus frames the basis for immunotherapeutic approaches. Immunotherapy seeks to induce a tumor-specific response, predicated upon a suitable target antigen, and its effective presentation.
In this article, we will discuss the upcoming trials and promising new immunotherapeutic drugs for advanced PCa, while highlighting some of the successes in PCa immunotherapy. These can be divided into cancer vaccines and immunomodulator treatment.
Sipuleucel-T is an active cellular immunotherapy, a type of therapeutic cancer vaccine consisting of autologous peripheral blood mononuclear cells, which includes ex vivo activated antigen-presenting cells (APCs) with a recombinant fusion protein fused to granulocyte-macrophage colony-stimulating factor (GM-CSF). The use of sipuleucel-T increased overall survival (OS) among men with metastatic castration-resistant prostate cancer (mCRPC) with a median 4.1-month survival improvement compared with placebo (25.8 months vs 21.7 months). Several other trials are testing combinations or sequencing of sipuleucel-T with radiotherapy and checkpoint inhibitors ipilimumab and atezolizumab.
DCVAC/PCa is an active cellular immunotherapy consisting of autologous mature dendritic cells (DCs) loaded with killed LNCaP cells (androgen-sensitive human prostate adenocarcinoma cells). A phase 1/2 clinical trial showed that DCVAC/PCa combined with docetaxel chemotherapy and prednisone in patients with mCRPC was safe, and resulted in longer than expected survival. The combination is currently in a phase 3 trial (VIABLE; NCT02111577), and recruitment has been completed. Another phase 1/2 trial of DCVAC/PCa in patients with rising prostate-specific antigen (PSA) after radical prostatectomy or salvage radiotherapy showed that the combination was safe, induced an immune response, and led to the notable prolongation of PSA doubling time.
PROSTVAC-VF(PSA-TRICOM) is a PCa vaccine regimen consisting of a recombinant vaccinia vector as a primary vaccination, followed by multiple booster vaccinations employing a recombinant fowlpox vector. Both vectors contain the transgenes for PSA and multiple T-cell costimulatory molecules (TRICOM). The PSA-TRICOM vaccines infect APCs and generate proteins that are expressed on the surface of the APCs. The interaction of these APCs with T cells initiates a targeted immune response and T cell-mediated tumor-cell destruction. In a phase 2 randomized controlled trial in mCRPC, PROSTVAC-VF immunotherapy was well tolerated and was associated with a 44% reduction in the death rate and an 8.5-month improvement in median OS. However, a phase 3 trial of PROSTAVAC-VF failed to confirm these benefits. This trial was stopped early after futility criteria were met. Combination therapy with immune checkpoint inhibitors is currently being explored in ongoing clinical trials.
GVAX (GM-CSF tumor cell vaccine) uses two PCa cell lines (PC‐3 and LNCaP) genetically modified to express GM-CSF and then irradiated for safety. An open-label, multicenter, dose-escalation study evaluated multiple dose levels of GVAX immunotherapy in patients with mCRPC and the vaccine was well tolerated; immunogenicity and OS varied by dose. However, two phase 3 trials involving GVAX-PCa, known as VITAL-1 and VITAL-2, were prematurely terminated due to a lack of therapeutic effect and increased mortality, respectively.
Listeria monocytogenes vaccine
A recombinant live attenuated L. monocytogenes/PSA vaccine was developed for the treatment of PCa. This recombinant bacterial vaccine was tested in a PCa murine model for stability, virulence, immunogenicity, and anti-tumor effects. It was shown to lower the number of tumor-infiltrating T-regulatory cells and cause complete regression of over 80% of tumors formed by an implanted genetically modified mouse PCa cell line. Two commercial Listeria platforms are currently being evaluated in phase I clinical trials for safety:
- ADU-741/JNJ-64041809 (alone; NCT02625857)
- ADXS31-142 (in combination with pembrolizumab; KEYNOTE-046.)
Preliminary data has shown a manageable safety profile but the vaccine warrants further study.
Pembrolizumab, a humanized antibody that inhibits PD-1, is approved for subsets of patients with advanced, MSI-high (or mismatch repair deficient (dMMR) variants of prostate cancer. Genomes of tumors that are dMMR are MSI-high and harbor somatic mutations that encode neoantigens. Therefore, these tumors are likely to be immunogenic, triggering the upregulation of immune checkpoint proteins. In a study by Abida et al, 3.1% of the 1033 PCa patients with evaluable disease had phenotypic evidence of MSI-H/dMMR, and 21.9% of these patients had a germline mutation in an MMR gene. Overall, 45.5% of patients with MSI-H/dMMR mCRPC derived durable clinical benefit. It is, therefore, essential to use the prospective tumor sequencing to screen all patients with advanced prostate cancer for MSI-H/dMMR because of the potential for durable responses to anti-PD-1/PD-L1 therapy.
Ipilimumab, a fully-humanized monoclonal antibody that binds and blocks CTLA-4, thus restoring an anti-tumor immune response, was approved in 2011 for advanced melanoma. Several clinical trials with this drug are ongoing for PCa. A pilot trial of CTLA-4 blockade with ipilimumab in mCRPC patients evaluated the pharmacokinetics and safety profile for Ipilimumab and to assess for PSA modulation and the development of polyclonal T-cell activation and/or clinical autoimmunity in mCRPC patients. Ipilimumab was found to be safe but did not result in significant clinical autoimmunity. In a phase 3 study, ipilimumab did not improve OS in mCRPC patients, but the noted increases in progression-free survival and PSA response rates suggested anti-tumor activity in a patient subset. Two large randomized clinical trials have now demonstrated that ipilimumab does not extend OS in unselected populations of patients with mCRPC but does result in measurable antitumor activity (see here and here). Future studies should be directed at evaluating how to utilize such anti-tumor activity and potential biomarker identification that may predict treatment benefit with ipilimumab.
Nivolumab is a human IgG4 anti-PD-1 agent and is FDA-approved for metastatic melanoma and other tumors. In advanced PCa patients treated with nivolumab, no objective responses were reported.
In Checkmate 650, combination therapy with nivolumab plus ipilimumab demonstrated activity in patients with advanced mCRPC, especially in those who had not received prior chemotherapy. Treatment-related toxicity was observed, with only 40% to 50% of patients able to receive the planned four cycles of treatment. An exploratory biomarker assessment showed a significant association between response and tumor mutational burden (TMB).
KEYNOTE-199 is a multicohort phase 2 study of patients with mCRPC who have previously progressed after docetaxel chemotherapy and at least one hormonal therapy. Cohorts 1–3 demonstrated modest objective response rates (ORR) via RECIST, but durable responses in those patients sensitive to pembrolizumab. The data from the remaining two cohorts, 4 and 5, were presented at the ASCO GU 2020 meeting. Cohorts 1–3 received pembrolizumab monotherapy, while 4 and 5 were given pembrolizumab added to enzalutamide. Responses were observed in a minority of patients but were durable. The combination of enzalutamide to pembrolizumab appears to demonstrate a higher ORR in those patients with measurable disease as compared to pembrolizumab alone, supporting the ongoing phase 3 clinical trial (KEYNOTE-641) of this combination in enzalutamide-naïve patients (see here and here).
KEYNOTE-365 is a non-randomized, open-label phase 1b/2 umbrella trial to evaluate the safety and efficacy of three treatment combinations in patients who have progressed on second-generation hormonal therapy and chemotherapy:
- Cohort A: pembrolizumab + olaparib
- Cohort B: pembrolizumab + docetaxel + prednisone
- Cohort C: pembrolizumab + enzalutamide.
Cohort A of KEYNOTE-365 included mCRPC patients who were treated with docetaxel and had PSA or radiologic bone/soft tissue progression within 6 months of screening. Pembrolizumab plus olaparib showed activity in this cohort, and the safety and tolerability profile of pembrolizumab plus olaparib was consistent with the individual profiles of each agent (see here).
The interim results of the COSMIC-021 phase 1b study of cabozantinib plus atezolizumab in mCRPC were presented at the ASCO GU 2020 meeting. The observed ORR at a median follow-up of 12.6 months with the combination was 32%. Cabozantinib plus atezolizumab led to a disease control rate of 80%, which included two complete and 12 partial responses. In a subgroup of high-risk clinical features patients, the ORR was 33%, and the median duration of response was 8.3 months. Among the 12 patients who achieved an objective response, 67% had a PSA decline of at least 50%.
Immune checkpoint inhibitor combination with a tumor vaccine may leverage complementary mechanisms of actions against PCa. A phase 1b trial evaluating the combination of atezolizumab plus sipuleucel-T in mCRPC showed a trend towards better radiographic progression-free survival with atezolizumab first, followed by Sipuleucel-T, and no unexpected adverse events were noted.
Adoptive T Cell therapy
Adoptive T cell therapy can cause an effective immune response against tumors, in which patients' T cells are reinfused after genetic engineering. In chimeric antigen receptor T-cell (CAR-T) therapy, the specificity of antibodies is associated with the cytotoxic activity of T cells to target tumor cells. Study results have shown that CAR-T is able to kill PSMA-positive PCa, which suggests that this novel immunotherapy treatment may offer a potential new approach for men with mCRPC.
Requirements for effective immunotherapy include an adequate number of immune cells that recognize a targeted antigen and ultimately elicit a tumoricidal effect. There are several immunotherapeutic strategies, some of which may include generating tumor-specific immune cells via a vaccine; however, a vaccine alone is less likely to induce ORR in mCRPC. Immune checkpoint inhibition may provide ORR in MSI-high mCRPC patients; hence, ongoing mCRPC patient trials continue with combinatorial approaches in order to broaden potential clinically activity.
About the authors