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12:00 AM
Jun 18, 2012
 |  BioCentury  |  Product Development

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 microenvironment, they are essentially tricked into not doing their job.

As a result, the next wave of compounds is based on the belief that the roadmap to containing cancer and making it a chronic disease is through a checkpoint inhibitor's ability to thwart cancer's evasive tactics, combined with something like a cancer vaccine that boosts T cell responses, and/or targeted small molecules with mechanisms that won't have a dampening effect on the immune system.

Back to the future

The upcoming Phase III data events are for cancer vaccines designed to stimulate a T cell response against tumors. Many of these products are allogeneic vaccines that could become the first off-the-shelf cancer vaccines approved in the U.S. (see "Late-Stage Cancer Vaccines," A9).

"I think the field is really looking to the results of the ongoing Phase III trials to show that one of these peptide vaccines can achieve the level of T cell activation to get above the necessary threshold," said Carsten Reinhart, CMO of cancer vaccines company immatics biotechnologies GmbH.

immatics' IMA901, a vaccine containing 10 tumor-associated peptides (TUMAPs), is in a Phase III trial in combination with Sutent sunitinib as first-line therapy for renal cell carcinoma (RCC). Results are expected in late 2013 or early 2014.

Pfizer Inc. markets Sutent, a small molecule VEGF receptor tyrosine kinase inhibitor to treat RCC, among other cancers.

Reinhart said IMA901 could succeed where other off-the-shelf products have failed, because the antigens it uses are more broadly present in tumors, and because immatics' application of mass spectrometry, genomics, biochemistry and immunology has allowed it to identify the conformation of the antigen that most closely resembles how it appears on cancer cells.

According to Reinhart, the result should be as strong an immune response as possible.

Other companies developing off-the-shelf vaccines with Phase III data events expected over the next couple of years include Kael-Gemvax Co. Ltd.; NovaRx Corp.; Merck KGaA and partner Oncothyreon Inc.; and Vical Inc.

Kael-Gemvax's GV1001 consists of a peptide sequence of human telomerase reverse transcriptase (hTERT), a catalytic subunit of the enzyme telomerase. A Phase III trial is evaluating GV1001 in metastatic and/or locally advanced pancreatic cancer; another Phase III trial is evaluating the product in advanced non-small cell lung cancer (NSCLC).

NovaRx's Lucanix belagenpumatecel-L...

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