Immunotherapy is at the forefront of cancer treatment and is changing the landscape of cancer therapeutics across all tumor types. Specifically in prostate cancer, immunotherapy has emerged as a viable and attractive treatment strategy. However, the promise of immunotherapy must be tempered with the reality of objective data. A review of rates of objective response in trials employing immunotherapy as monotherapy in both lung cancer and melanoma shows response rates of only 20%â30% at best, leaving much to be desired in terms of patient benefit (1, 2).
One of the most compelling areas of study in immunotherapy is the effect of combining immunotherapeutic approaches, a process known as immunogenic intensification. Combining vaccine with immune checkpoint inhibitors highlights the potential of combining immunotherapies to generate a greater immune response and enhance tumor killing.
Prostate cancer is an ideal candidate for immunotherapy. Prostate cancer cells express several tumor-associated antigens (TAAs), including prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), and prostate-specific membrane antigen. These TAAs are ideal targets for activated immune cells (3). The landmark FDA approval of sipuleucel-T (ProvengeÂ®), an autologous antigen-presenting cell vaccine designed to target PAP for minimally symptomatic or asymptomatic metastatic castration-resistant prostate cancer (mCRPC) (4), has set the stage for the use of therapeutic cancer vaccines either as monotherapy or in combination with other cancer treatments.
PROSTVACÂ®, another active immunotherapy, is composed of a series of poxviral-based vectors that express PSA. PROSTVAC immunotherapy is based on a prime-boost regimen wherein the first vaccination uses a vaccinia vector to prime the immune system, while subsequent boost vaccinations are fowlpox-based. This regimen is designed to optimize the immune response by exposing the immune system to the same antigens while using different vectors. The vectors also express B7.1, ICAM-1, and LFA-3, a triad of human T-cell costimulatory molecules known as TRICOM. In early studies, PROSTVAC was well tolerated with minimal toxicity. The vaccine is currently being evaluated in an international phase III randomized, controlled trial.
Following the success of ipilimumab (YervoyÂ®) in metastatic melanoma, this first-in-class immune checkpoint inhibitor is also being evaluated as a monotherapy in a phase III trial in chemotherapy-naÃ¯ve patients with mCRPC. While a previous phase III trial of ipilimumab in the post-docetaxel setting failed to meet its primary endpoint of overall survival (OS) (5), there was a trend toward improved survival (11.2 months vs. 10 months for placebo; HR 0.85; p = 0.053). Post hoc subgroup analysis suggested that patients with indolent disease features who received ipilimumab had a substantial improvement in OS, which is encouraging given the ongoing trial in earlier-stage disease. This trial (NCT01057810) has completed accrual and results are eagerly anticipated.
Therapeutic cancer vaccines can induce an immune response, which in turn can lead to killing of tumor cells. Even patients with no underlying antitumor immune response may benefit from a therapeutic cancer vaccine. Unfortunately, this is not the case for immune checkpoint inhibitors like ipilimumab and anti-PD-1/PDL-1, which require an underlying immune response to be clinically active. However, combining a therapeutic vaccine with an immune checkpoint inhibitor can unleash underlying, but previously ineffective, immune responses. Preclinical models have demonstrated synergy between cancer vaccines and immune checkpoint inhibitors. In many weakly immunogenic tumor models, treatment with immune checkpoint inhibitors targeting CTLA-4 and anti-PD-1 actually enhances the amplitude of vaccine-induced antitumor immune responses (6).
Early safety and efficacy studies of ipilimumab plus vaccine opened the door for future trials of combination therapy with immune checkpoint inhibitors (7). A study comparing data from three independent trials of PROSTVAC was featured at the 2015 ASCO Genitourinary Cancers Symposium (8). In two separate phase II trials, patients with mCRPC treated with PROSTVAC alone had improved OS. In one multicenter phase II trial, 125 men were randomized 2:1 to receive PROSTVAC or a wild-type vector placebo. Patients treated with vaccine had a median OS of 25.1 months compared with 16.6 months in the placebo group (HR 0.56; 95% CI 0.37â0.85). The second trial, which included 32 men, showed a median OS of 26.6 months vs. the Halabi-predicted mean OS of 17.4 months. A phase I combination study of 30 patients with mCRPC (and baseline characteristics similar to those in the phase II trials of PROSTVAC alone) employed vaccine plus escalating doses of ipilimumab. Follow-up was about 80 months. Updated survival data from this trial show a median OS of 31.3 months for all dose cohorts and 37.2 months for patients treated at the highest dose (10 mg/kg). Furthermore, there appears to be a tail on the curve, with approximately 20% of patients at 10 mg/kg alive at 80 months.
These hypothesis-generating data suggest a rationale for combining vaccine and immune checkpoint modulation, as well as for combining prostate cancer vaccines with monoclonal antibodies targeting PD-1. Agents targeting PD-1 and PDL-1 have been associated with fewer side effects than CTLA-4 inhibitors, and thus are of interest for combination therapy. However, to date there have been few studies of these agents in patients with prostate cancer. Interestingly, although PDL-1 expression has been reported in fewer than 1% of prostate tumor samples (9), one study found that prostate cancer cells that were PDL-1-negative were surrounded by PD-1-positive and PDL-1-positive immune cells . Thus, therapeutic cancer vaccines may enhance the efficacy of immune checkpoint inhibitors in prostate cancer and broaden the patient population who may benefit from this combination therapy.
Cancer vaccines are designed to activate immune cells, while immune checkpoint inhibitors increase T-cell activation and tumor killing by blocking immunoregulatory mechanisms. The fact that high-avidity cytotoxic T-lymphocytes may have more pronounced antitumor efficacy provides additional justification for combining immune checkpoint blockade with immunotherapy for patients with prostate cancer. Put simply, combining immune checkpoint inhibitors with PROSTVAC provides directed T-cell activation while removing physiologic brakes from the immune system, allowing for a more robust cytotoxic T-lymphocyte response.
The promise of immune intensification must be balanced by considerations of toxicity. Recent results showing improved clinical response in patients with advanced melanoma who were treated with nivolumab combined with ipilimumab were met with great enthusiasm. However, the combination treatment also showed increased toxicity, more than doubling the rate of grade 3 and 4 toxicities in treated patients. The most common toxicities were rash, diarrhea, and fatigue; three deaths were related to the combination therapy, according to investigator assessment (12). On the other hand, combining a vaccine such as PROSTVAC, which is associated with minimal toxicity, with agents targeting PD-1 and PDL-1 may improve outcomes while maintaining a manageable toxicity profile. More trials are required to truly evaluate this potential, but one thing is clear: immune checkpoint inhibitors have compelling and durable activity in a proportion of patients. Intensifying immunotherapy is one way to increase that proportion of patients. Perhaps therapeutic cancer vaccines are the savior these agents needâimproving outcomes by exploiting synergy.
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11. Postow M.A., et al., Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma. N Engl J Med, 2015 Apr 20 [Epub ahead of print].
Harpreet Singh, MD.
Genitourinary Malignancies Branch, National Cancer Institute, National Institute of Health , Bethesda, MD , USA.