Optimizing Immunotherapy in the Cold Prostate Cancer Microenvironment

Optimizing Immunotherapy in the Cold Prostate Cancer Microenvironment


Dr. Ravi A. Madan

Dr. James L. Gulley

By Ravi A. Madan, MD, and James L. Gulley, MD, PhD

Article Highlights

  • The prostate cancer tumor microenvironment may lack a sufficient immune presence, which could explain why immune checkpoint inhibitors have been ineffective as monotherapy in prostate cancer.
  • Therapeutic cancer vaccines may be one option to drive immune cells to the tumor microenvironment through activation against a specific tumor antigen.
  • Using immunotherapy earlier in the disease process when tumor volume and associate immune-suppressive mechanisms are lower may be advantageous.
  • The immunotherapeutic strategies that may yield the greatest impact on patients may require multiple strategies combined together, including vaccines, immune checkpoint inhibitors, and immunocytokines.

Although sipuleucel-T was approved by the U.S. Food and Drug Administration in 2010 based on an overall survival advantage,1 prostate cancer appears to have been left out of the subsequent immunotherapeutic revolution in medical oncology, which has largely been fueled by immune checkpoint inhibitors.2

Two trials with ipilimumab in metastatic castration resistant prostate cancer (mCRPC), prior to and following chemotherapy, were negative for a survival advantage.3,4 Similarly, multiple small studies with anti–PD-1 and anti–PD-L1 therapies have yielded modest results.5 The National Cancer Institute (NCI) is currently exploring multiple strategies to enhance the efficacy of immunotherapy in prostate cancer. These studies are not just important to the field, but could have implications across all tumor types, providing a means to expand the subgroup of patients who respond to immune checkpoint inhibitors as monotherapy.

One likely obstacle in generating antitumor immune responses is that the immunologically “cold” prostate cancer microenvironment may be devoid of sufficient immune cells to make PD-1/PD-L1 inhibition a viable strategy.6 Therapeutic cancer vaccines may be one option to drive immune cells to the tumor microenvironment through systemic activation initially against a specific tumor antigen. Proof of concept for this study was demonstrated in a neoadjuvant study conducted with sipuleucel-T, which was given prior to radical prostatectomy.7 There were increased immune cells relative to baseline biopsies noted at the periphery of the tumor when the prostate was resected, suggesting peripheral activation of immune cells via sipuleucel-T indeed did drive immune cells to the tumor microenvironment.7

Vaccines in Immunotherapy

A trial underway at NCI is looking to exploit the therapeutic potential of sipuleucel-T. In this trial (NCT02933255), patients will be treated with the therapeutic vaccine PROSTVAC, a poxviral-based vaccine targeting prostate-specific antigen (PSA) in the neoadjuvant setting with a planned combination of ipilimumab (1 mg/kg) and standard dosing of nivolumab. The primary focus will be to explore the immunologic changes in the tumor microenvironment after the combination strategy is used prior to surgical resection. A safety cohort (10 patients) in mCRPC is nearly complete, and data from that cohort will likely be presented later this year. If either cohort demonstrates clinical efficacy, it could help redefine the role of immune checkpoint inhibitors and vaccines in prostate cancer, with application to other tumors.

Another strategy is to deploy immunotherapy earlier in the disease process when tumor burden and related immune suppressive mechanisms may also be significantly lower than in advanced, large-volume metastatic disease. Patients with prostate cancer present a unique opportunity to evaluate this type of disease state. Patients with biochemical recurrence have been treated with definitive radiation or surgery, but unfortunately were not cured. These patients have recurrent disease (likely in the form of micrometastatic disease) that can be detected by a rising serum PSA often years before conventional imaging (bone scans and CT scan) is able to detect disease.

A study is currently accruing at NCI, in collaboration with Memorial Sloan Kettering Cancer Center and the
Dana-Farber Cancer Institute, evaluating PROSTVAC as monotherapy in biochemically recurrent prostate cancer (NCT02649439). This is based on a previous study that suggested that PROSTVAC could slow the PSA rise in biochemically recurrent prostate cancer.8 Preliminary results will be presented at the 2018 Genitourinary Cancers Symposium in February (Abstract 215); however, based on the findings thus far, another study will be conducted with escalation of the immunotherapeutic intervention in this population (NCT03315871). This study will evaluate PROSTVAC for 4 months with an additional vaccine, CV-301, a poxviral vaccine which targets CEA and MUC1, which are also relevant tumor antigens in prostate cancer. After 4 months, the bifunctional antibody M7824 will be added to the vaccine combination.9 This agent binds to PD-L1 (as an inhibitor) while also containing a TGF-beta neutralizing trap component. Once the safety of this combination is confirmed in mCRPC, this combination will help determine the potential of this type of immunotherapeutic strategy in early cancer recurrence/micrometastatic disease.

An ongoing study at NCI is combining the PARP inhibitor olaparib with anti–PD-L1 inhibitor durvalumab in patients with mCRPC who have not been selected based on DNA damage repair mutation status (NCT02484404). Preliminary data suggests that this combination may have some immunologic synergy given that responses are seen beyond patients known to harbor DNA damage repair mutations, which are known to respond to PARP inhibition.10 Of the first 17 patients, 10 patients have responded, with only six of those known to have DNA damage repair mutations.11 These data suggest that of the 10 patients responding (defined as partial response radiographically or by the standard metric of greater than 50% PSA decline), four patients do not have known DNA damage repair mutations. The median progression-free survival (PFS) is also noteworthy at greater than 12 months, which is longer than seen in the sentinel paper where unselected patients with mCRPC were treated with olaparib alone.10 Expected PFS in this population (patients with mCRPC who had progressed on frontline antiandrogen therapy) on standard therapies alone would be no greater than 5 months.12 An additional 40 patients are planned to enroll on this study to confirm these preliminary findings and better understand the potential underlying mechanism of synergy between these two treatment strategies.

Safety First

Ultimately, the immunotherapeutic strategies that may yield the greatest impact on patients may require multiple strategies combined together, including vaccines, immune checkpoint inhibitors, and immunocytokines. Unlike with conventional cytotoxic therapies or chemotherapies, the relatively minimal toxicity profile characteristic of these strategies may allow for these combinations to be easily deployed in the clinic. To that end, an innovative adaptive study design is planned for prostate cancer that will evaluate safety and preliminary evidence of efficacy in sequential cohorts. Cohort 1 will evaluate a vaccine targeting the transcription factor brachyury (implicated as a driver of epithelial to mesenchymal transition and drug resistance) with the bifunctional antibody M7824, targeting both PD-L1 and TGF-beta.9,13 Six to 12 patients will be evaluated for safety, and if there are more than two patients with clinical responses in this cohort, it will be expanded to 35 patients to further evaluate efficacy of this combination. Once safety is confirmed, the next cohort will build on this combination of vaccine and bifunctional immune-checkpoint inhibitor, with the addition of the immunocytokine ALT-803 and IL-15 superagonist, which has demonstrate preclinical evidence of synergy with M7824.14

Again, six to 12 patients will be evaluated for safety and preliminary efficacy with the same signal required (two responders) to expand the cohort. The third cohort will launch after safety of the previous cohort and evaluate the vaccine/M7824/ALT-803 combination with epacadostat, an indoleamine 2,3-dioxygenase 1 inhibitor that has been developed to overcome immune suppression in the tumor microenvironment and has demonstrated potential synergy with PD-1/PD-L1 inhibition.15,16 This strategy is designed to rapidly evaluate safety and clinical efficacy of a number of immunotherapy combinations in prostate cancer to confirm safety and identify strategies that can be moved into advanced trials.

Immunotherapy has not expanded as rapidly in prostate cancer in recent years relative to other malignancies, likely due to the fact that the immune checkpoint inhibitor monotherapy cannot enhance outcomes because of an absence of baseline immune recognition within the tumor microenvironment. Multiple immunotherapy strategies are currently under investigation to enhance immune infiltration of the tumor or overcome immune suppression within the tumor using vaccines and immunocytokines in combination with immune checkpoint inhibitors. If these strategies are successful, they will have broad implications beyond prostate cancer and potentially augment the immunotherapeutic potential for all patients with cancer.

About the Authors: Dr. Madan is the Clinical Director of the Genitourinary Malignancies Branch at the National Cancer Institute. Dr. Gulley is the Chief of the Genitourinary Malignancies Branch at the National Cancer Institute.