Figure 1 – SIPLULEUCEL-T phase 3 study demonstrating clinical survival benefit:
Ipilimumab, analyzed in two phase 3 studies1,2 did not show any survival benefit in this tumor (Figure 2). The KEYNOTE-199 study analyzed the role of pembrolizumab for post-docetaxel MCRPC patients (Figure 3). The overall conclusion from this trial was that pembrolizumab had antitumor activity and acceptable safety in these patients. Its activity was observed both in PD-L1 positive and PD-L1 negative cohorts. Its activity was also observed in patients with RECIST-measurable disease and in those with bone- predominant disease. In this trial, the response rate was low, with a complete and partial response of less than 5%. All responders underwent genomic analysis with whole exome sequencing. A total of 6/9 responders had available data. Four out of these 6 patients had mutations in the DNA damage repair genes (DDR).
Figure 2 – Ipiimumab in prostate cancer:
Figure 3 – Keynote 199 study design:
Unfortunately, there is a great need for data showing clinical benefit for ICI in PC. The mechanism by which tumor cells deal with the immune system is depicted in Figure 4.
Figure 4- How do tumors deal with the immune system:
The reason ICI is ineffective in PC is most probably due to the fact that the majority of cancer patients lack sufficient immune cells in the prostate microenvironment. However, this is potentially a modifiable microenvironment. This can be done through activation of immune cells in the periphery and enable them to travel to the tumor microenvironment, through vaccines, immunocytokine, and some cytotoxic therapies. This resulted in the application of combination therapies because it is known that vaccines for example, can increase tumor infiltrating lymphocytes in the tumor microenvironment, which is associated with treatment response to the PD-1 blockade.
The possible strategies to enhance immunotherapeutic benefit in PC include:
- Combination immunotherapies
- Multiple vaccines
- Vaccine + ICI
- Immunocytokine + ICI
- Combination with therapies to capitalize on potential immunologic synergy, as these added therapies can induce immunogenic modulation:
- Enzalutamide
- PARP inhibition
- RADIUM 223
- Docetaxel
In conclusion, immunotherapy has a limited role in PC. Future strategies require altering the tumor microenvironment to make it more responsive to immune killing. Combinations with chemotherapy, radiation or immunotherapy may optimize immune activation. Lastly, earlier stages of PC with less tumor burden and normal testosterone may have different responsiveness to immunotherapy compared to the MCRPC state.
References:
1. Kwon ED et al. Lancet Oncol 2014
2. Beer TM et al. J Clin Oncol 2017
Presented by: Raanan Berger, MD Sheba Medical Center, Israel
Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at the 2018 FOIU 4th Friends of Israel Urological Symposium, July 3-5. 2018, Tel-Aviv, Israel