Immunotherapies: Avoiding collisions once the brake is released

Immunotherapies again made headlines in oncology last month when the Centers for Medicare and Medicaid Services (CMS) decided that the anticancer vaccine sipuleucel-T (Provenge^®) will be a payable expense for prostate cancer. The CMS decision came days after another anticancer vaccine, ipilimumab (Yervoy^TM),received approval from the Food and Drug Administration (FDA) as treatment for patients with advanced melanoma.

In clinical trials, sipuleucel-T increased survival by 4.1 months, but with a price tag of $93,000 many view the treatment as exorbitant cost-wise. However, some physicians and researchers think that this treatment and upcoming vaccines will provide unprecedented options in treating patients with advanced-stage prostate cancer.

At last month’s Interdisciplinary Prostate Cancer Congress (IPCC), A. Oliver Sartor, MD, medical director, Tulane Cancer Center in New Orleans, LA, discussed integrating novel immunomodulatory therapies into treatments for advanced prostate cancer. “I think sipuleucel-T is incredibly important from the perspective of being a proof of concept,” Sartor said.

Sartor has led a number of large, international phase 3 trials in prostate cancer and has focused on novel therapeutics for advanced prostate cancer patients for over 20 years.

The approval of Sipuleucel-T has propagated further research in immunotherapy (Figure 1). Ipilimumab was approved March 25 for the treatment of metastatic melanoma. Ipilimumab is now in phase 3 trials for the treatment of chemotherapy-naïve and post-docetaxel chemotherapy-recurrent forms of metastatic, castration-resistant prostate cancer (mCRPC). It works by blocking the CTLA-4 antigen, a critical negative regulator of the antitumor T-cell response.

Releasing the Brakes

According to an article by Tarhini A, et al (Cancer Biother Radiopharm. 2010 Dec;25(6):601-613.), one of the most promising strategies to support and enhance the patient’s natural antitumor response consists in blocking the immunoregulatory mechanisms that brake host responses to tumor-associated antigens (TAAs), thereby—therapeutically—releasing the brakes.

Once this brake is released, however, it also releases immune-related toxicities that can lead to dangerous adverse events in some patients. Ipilimumab carries a black box warning that details possible severe and fatal immune-mediated adverse reactions from T-cell activation and proliferation. Most common adverse reactions for ipilimumab (≥5%) are fatigue, diarrhea, pruritus, rash, and colitis.

“Under ideal circumstances, we might try to control this by presenting additional antigens, but that is a concept that we don’t have in place yet,” Sartor said. “Maybe we need to utilize a sipuleucel-T-type strategy, and then augment the immune reaction. That’s theoretical, it’s not proven, but when you look at the mechanism of action you think about how to add specificity. One way that you might be able to do that is through radiation.”

A phase 2 study of ipilimumab studied patients taking 10 mg/kg of ipilimumab; a second cohort added radiation therapy to this treatment; and a third cohort involved patients who were postchemotherapy, with radiation therapy and 10 mg/kg of ipilimumab. Significant reductions in immune-related adverse events were seen in the second arm of the study (Figure 2).

“There were also some pretty provocative results with regard to prostate-specific antigen(PSA) declines,” Sartor said, while noting that nonspecific treatments such as ipilimumab can still pose dangerous and potentially fatal consequences. “You have to realize that when you are activating the immune system nonspecifically, you have to be very careful about the consequences,” he said.

Investigational Immunotherapies

Sartor also discussed the investigational vaccine PROSTVAC^®-VF, which contains 3 costimulatory molecules to enhance T-cell activation (Figure 3). The vaccine is delivered as an injection derived from mammalian cells and is able to induce an immune response, eliminating the need for leukapheresis. This agent is scheduled to begin phase 3 trials in late summer, in 1200 patients with minimally symptomatic mCRPC. According to an analysis of phase 2 data, PROSTVAC^®-VF was well tolerated and associated with a 44% reduction in death rate and an 8.5-month improvement in median overall survival (OS) in men with mCRPC.

The final immunotherapy that Sartor discussed was BPX-101, a dendritic cell (DC) vaccine intended for patients with mCRPC. This vaccine is comprised of mature, antigen‐expressing DCs derived from monocytes collected during outpatient leukapheresis. It is then developed by manipulating the survival and activation state of the autologous DC in situ (Figure 4). During this process, the cells are modified so that a proprietary drug (AP1903) can activate the vaccine for a timed response. According to Bellicum Pharmaceuticals, the company developing the vaccine, “BPX-101 is administered intradermally, followed 24 hours later by a 2-hour infusion of AP1903. This 1-day delay gives the cells time to migrate to the patient’s lymph nodes, where they are activated by AP1903—in the right place and at the right time to drive a maximal anticancer immune response.”

Sartor says the vaccine has shown significant tumor responses. A phase 1/2 clinical trial of BPX-101 included scans of a patient with mCRPC after docetaxel chemotherapy, metastatic to lungs, lymph nodes, and bone, with a Halabi‐predicted survival of 12.5 months. The patient was treated with 6 doses of BPX‐101 starting 6 weeks after baseline scans. Six measurable metastatic lesions in the lungs were eliminated by the end of the 12-week induction phase of treatment (20 weeks after baseline scans). Metastases at other sites were stable at 12 weeks. He remains alive with progressive disease 10 months after enrollment.

Potential synergy between BPX‐101 and docetaxel chemotherapy, with single or more limited dosing, will be further explored in a phase 1 extension study. A phase 2 clinical trial using BPX‐101 and AP1903 is now enrolling patients.

When considering cost, convenience, safety, and specificity, no ideal immunotherapy or strategy has been approved for patients with prostate cancer. But recent advancements have shown that each new therapy offers promise that further treatments may someday make prostate cancer a chronic condition rather than a deadly disease.

All Slides Courtesy of A. Oliver Sartor, MD