Immune springboard

New wave of cancer immunotherapies using biological insights from BMS's Yervoy

A spate of Phase III data events over the next two years will give a readout on how correctly the lessons learned five years ago about cancer immunotherapies targeting T cell responses have been put into practice. But the next wave of therapies already is testing and building upon new insights brought about by the success of Yervoy ipilimumab, the first of the immune checkpoint inhibitors.

Dendreon Corp.'s Provenge sipuleucel-T, which was approved to treat metastatic castration-resistant prostate cancer (CRPC) in 2010, proved the longstanding hypothesis that it is possible to induce a cancer patient's T cells to mount enough of a response against tumors to produce a measurable clinical effect (see BioCentury, April 20, 2009).

However, the autologous dendritic cell therapy requires a complicated manufacturing process and at the median extends patient survival by only 4.5 months.

Over the next 30 months, at least eight immunotherapies focused on inducing T cell responses against tumors will have Phase III data. Researchers and clinicians contacted by BioCentury believe these studies have good to modest chances of achieving statistical significance.

Yet these readouts will tell more about the validity of Provenge-era insights and strategies - such as enrolling earlier-stage immunocompetent patients, improving antigen presentation and selection, and shifting clinical endpoints from response rates to survival - all of which were adopted years ago based on a generation of immunotherapies that failed in the late '90s and early '00s (see BioCentury, May 29, 2006).

Meanwhile, the approval of Bristol-Myers Squibb Co.'s Yervoy has provided a new set of lessons about a complementary approach to immunotherapy that involves knocking down a tumor's ability to shield itself from the immune system.

Yervoy, a mAb against CTLA-4 (CD152), was approved in 2011 for metastatic melanoma. The drug produces durable responses, but only in a small fraction of patients.

In addition, the nonspecific nature of the immune response Yervoy generates often causes significant autoimmune-related side effects. Its label contains a boxed warning about the risk of severe and fatal immune-mediated adverse reactions due to T cell activation and proliferation that occurred in 15% of patients who received the drug in a Phase III trial.

Nevertheless, there is now increased recognition that cancer's ability to promote immune tolerance means that, for many patients, the number of T cells capable of killing tumor cells does not determine outcomes. That is because as soon as the T cells arrive in the tumor

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