Immunotherapy: A Glimmer of Hope for Metastatic Prostate Cancer

Vishal Jindal

Disclosures

Chin Clin Oncol. 2018;7(6) 

In This Article

Combination Therapies

Vaccines With Immune Checkpoint Inhibitors

Immune check point inhibitors have significantly failed in improving clinical outcome in prostate cancer patients. There was no improvement in OS with ipilimumab and nivolumab, but the progression free interval improved. It depicts that, there was response, but not up to that extent to become statistically significant. The other likely reason for failure of immune checkpoint inhibitors is not enough inflammation and T cell infiltration in microenvironment of the tumor to cause immune activation and destruction of cancer cells. Vaccine on the other hand didn't improve PFS but OS improved and with Sipuleucel-T, there is increase in T cell infiltration and inflammation in microenvironment of tumor. Therefore, there should be synergistic effect in combination of vaccines and immune checkpoint inhibitors.

A clinical trial of combination of ipilimumab and therapeutic cancer vaccine Prostvac has shown preliminary evidence of improvement in clinical and immunologic outcome. The median OS was 34.4 months[53] which as compared to Prostvac alone in contemporary study was 26.3 months.[54] There was reduction in PSA in 54% of patients and PSA decline more than 50% was seen in 25% of patients. This study suggests potential synergy between vaccines and Immune check point inhibitors. Further studies are going on combination therapy of vaccines and immune checkpoint inhibitors which have been shown in Table 1, Table 2, Table 3, Table 4 and Table 5.

Combination of Immune Checkpoint Inhibitors

Anti CTLA-4 and anti PD-1 both are immune checkpoint inhibitors, but act on different receptors and affect the immune response in different ways, therefore, they may have synergistic effect when combined together. Ipilimumab and nivolumab combination therapy have been tested in Melanoma, which showed improved outcomes as compared to independent therapies of both. But there were grade 3 to 4, adverse reaction in 55% of population.[55,56] Currently phase 1 and phase 2 studies are going on regarding combination therapy in CRPC, which have been described in Table 3 and Table 4. But increased efficacy of the combination has to weighed against increased side effect profile.

Combination of Immunotherapy With Standard Therapy (Chemotherapy and Radiotherapy)

Standard therapy reduces the tumor burden by killing the cancer cells. This lysis and degradation of cancer cells release potent cancer antigens which if picked by immune system can lead to activation of T cells and further lysis of cancer cells. But this doesn't happen as cancer cells modify immune system accordingly and suppress immune activation. If immunotherapy is used with standard therapy, suppression of immunity by cancer cells will be reduced and there will be enhanced activation of immune system which leads to proliferation of T cells and lysis of tumor. Androgen deprivation therapy attenuate immune response, enhance thymic output of naïve T cell, promotes T cell trafficking to prostate and improves tolerance and all of this provides a prime rationale for synergism with immunotherapy.[57–60] In preclinical studies it has been shown that chemotherapy (docetaxel) enhances the major histocompatibility complex 1 (MHC-1) and tumor antigen expression and even low dose of radiotherapy does the same.[59,61–64] Currently various initial phase trials are going on regarding this combination therapy which have been summarized in Table 1, Table 2, Table 3, Table 4 and Table 5.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....