Framework Proposed for Immunotherapy Studies

Cancer immunotherapy, which marshals a patient's immune system to attack malignant cells, has long been modeled and assessed by the same criteria used for chemotherapy despite distinct differences between these 2 treatment methods.

But in a recent letter (Nat Biotechnol 2011;29:867–70), the Cancer Immunotherapy Consortium of the Cancer Research Institute and the Association for Cancer Immunotherapy outline a methodologic framework to recognize these differences and ultimately to speed such treatments.

As the letter describes, immunotherapy differs from chemotherapy in 5 key ways:

• The optimal biologic dose is often not the maximum tolerated dose.

• Treatment effect is not proportionally linked to toxicity.

• Conventional pharmacokinetics may not determine dose and schedule.

• Anti-tumor response is not the sole predictor of survival.

• Clinical effects can be delayed and can occur after tumor volume increase.

In addition to improving immunotherapy study design, the proposed framework seeks standardized criteria to measure immune response and develop biomarkers, as well as a more formal network to monitor trial results. The authors call on regulatory authorities to guide this new paradigm.

Approvals of 2 immune-based drugs in recent years have bolstered this emerging field. The first, the therapeutic vaccine sipuleucel-T (Provenge; Dendreon), treats hormone-refractory prostate cancer. The second, a drug for metastatic melanoma, ipilimumab (Yervoy; Bristol-Myers Squibb), is a monoclonal antibody that works by interfering with immunologic checkpoints that slow or stop immune cell activation.

Ipilimumab's approval illustrates the complexity of designing and evaluating immunotherapy trials. A very similar monoclonal antibody, tremelimumab (CP-675,206; Pfizer), failed in phase III trials, but a 2-year follow-up revealed higher survival rates among patients who received the drug. Consequently, the ipilimumab trial set endpoints based on overall survival, instead of response rate and progression-free survival as used for tremelimumab.

“The letter raises issues crucial to the future of immunotherapy, such as when and what to measure to gauge a treatment's success,” says Howard Streicher, MD, a senior investigator in the Investigational Drug Branch at the National Cancer Institute's Cancer Therapy Evaluation Program. “It's a very dynamic and exciting field, but we clearly still have a lot to learn.”

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