Immunotherapies: Avoiding Collisions Once the Brake Is Released

Sandra Kear
Published: Saturday, Jun 11, 2011
Figure 1. Process of vaccination development and delivery with sipuleucel-T.Immunotherapies made headlines in oncology last month when the Centers for Medicare & 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), 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 cost as exorbitant. However, some physicians and researchers think that this treatment and upcoming vaccines will provide unprecedented options in treating patients with advancedstage prostate cancer.

At the 2011 Interdisciplinary Prostate Cancer Congress held in March, A. Oliver Sartor, MD, medical director, Tulane Cancer Center in New Orleans, Louisiana, 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 III 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 III trials for the treatment of chemotherapy-naïve and postdocetaxel 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 et al, one of the most promising strategies to support and enhance the patient’s natural antitumor response consists of blocking the immunoregulatory mechanisms that brake host responses to tumor-associated antigens, thereby— therapeutically—releasing the brakes (Cancer Biother Radiopharm. 2010;25:601-613).

Figure 2. Adverse events from phase 2 trial of ipilimumab combined with radiation therapy.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 immunemediated 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 II 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).

Figure 3. Schematic of PROSTVAC-VF action “There were also some pretty provocative results with regard to prostate-specific antigen declines,” Sartor said, while noting that nonspecific treatments such as ipilimumab can still have 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 III trials in late summer, in 1200 patients with minimally symptomatic mCRPC. According to an analysis of phase II 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 in men with mCRPC.

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TitleExpiration DateCME Credits
Clinical Interchange™: Translating Research to Inform Changing Paradigms: Assessment of Emerging Immuno-Oncology Strategies and Combinations across Lung, Head and Neck, and Bladder CancersOct 31, 20182.0
35th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow® Clinical Vignette SeriesJan 31, 20192.0
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