Dogma: Is Cancer a Genetic disease or an Immunologic Disorder?

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http://www.medscape.com/viewarticle/782105

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WASHINGTON, DC — In a noteworthy moment in the history of cancer drug development, phase 3 clinical trials of an experimental agent are simultaneously underway in 3 different cancer types.
Trials of the investigational immunotherapy nivolumab (Bristol-Myers Squibb) have begun in melanoma, renal cell carcinoma, and nonsmall-cell lung cancer, said Suzanne Topalian, MD, here at the annual meeting of the American Association for Cancer Research (AACR) 104th Annual Meeting. She is from the Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland.
The simultaneous trials of a single investigational agent in so many different cancers “may be unprecedented,” Dr. Topalian told Medscape Medical News in an interview.
The phase 3 trials are an outgrowth of the positive results seen in phase 1 trials of nivolumab, which was previously called BMS-936558 and MDX-1106. The agent is a monoclonal antibody that neutralizes the programmed death 1 (PD-1) protein, an element of tumors that enables them to evade their nemesis, the immune system.
Nivolumab was hailed as the next big thing in cancer treatment last year after early data indicated that it had durable tumor response rates of 20% to 30% in multiple cancers. In the words of one expert, the agent had “broken the ceiling” of durable tumor response rates of 10% to 15% that has existed for cancer immunotherapies over the past 30 years.

That an immunotherapy — and not some other type of cancer treatment — should be making such an auspicious debut in phase 3 trials is not an accident, Dr. Topalian noted.
“In many ways, the adaptive immune system comprised of T-cells and antibodies is an ideal anticancer agent,” she told the audience at a plenary session.
Dr. Topalian challenged the prevailing wisdom in cancer research.

“The current dogma is that cancer is a genetic disease,” she explained, acknowledging that individual tumors contain hundreds of mutations and alterations in signaling pathways, which are the basis of the personalized medicine approach.

But the genetic model is highly problematic, she argued. The problem of resistance to targeted therapies “has its limitations,” she noted. “Blocking one pathway can lead to the emergence of another,” she explained.

An “alternative viewpoint” proposed by Dr. Topalian is that “cancer is an immunologic disorder.”

Immunotherapy is the “common denominator” that “takes advantage of the fact that many of the mutations of cancer can be specifically recognized and targeted by the immune system.” Furthermore, “the immune system can adapt and evolve as the cancer evolves,” she said.

Dr. Topalian showed a timeline of the identification of the PD-1 gene and the development of an anti-PD-1 therapy (Nat Immunol. 2012;13:1129-1132). The timeline, which was not created by her research team, projects US Food and Drug Administration approval of anti-PD-1 therapies by 2015.

“If nivolumab is approved, it would be so inspiring and motivating for the field of immunology,” said Priyanka Agharkar, a predoctoral trainee from the Department of Cell Stress Biology at the Roswell Park Cancer Institute in Buffalo, New York. Aside from sipuleucel-T (Provenge) for prostate cancer and ipilimumab (Yervoy) for melanoma, “there is very little approved in terms of immunotherapies for cancer,” she told Medscape Medical News.

There is now plenty of competition in the field of anti-PD-1 agents and complementary anti-PDL1 agents. In fact, Genentech, Amplimmune/GSK, CureTech, Merck, and MedImmune all have drug development programs.

Proof From 3 Patients That the Immune System Has “Memory”

The quality that makes the immune system “different from all other cancer therapies” is that the immune system has “memory,” said Dr. Topalian.

To support her assertion, she showed treatment and response timelines for 3 of 39 patients treated with nivolumab in the first-in-human trials for melanoma, renal cell carcinoma, nonsmall-cell lung cancer, prostate cancer, and colorectal cancer.
The 3 patients had objective responses for a “very long time” after a single course of treatment with nivolumab, she reported.
A patient with colorectal cancer had a complete response after a few months of treatment, which has remained into year 4 after initiation of treatment.
A patient with kidney cancer had a partial response after a few months of treatment; the tumor continued to shrink and a complete response was seen in year 3 after treatment.The patient has maintained the response into year 4.
A melanoma patient had a partial response and was taken off treatment after a few months. In year 3 after trial enrollment, that patient had lymph node metastases and resumed treatment, but has achieved an ongoing partial response into year 4.
In addition, in a follow-up phase 1 trial of nivolumab, durable tumor regressions were seen in approximately 300 patients with lung cancer, melanoma, and kidney cancer, and regressions persisted even after the drug was discontinued.
These results are “compatible” with the idea that the immune system has a memory, said Dr. Topalian.
“This is actually a living therapy that stays with the host, potentially for years,” she noted.
She explained that the duration of the effect could be similar to childhood vaccines for infectious diseases, and the resulting immunity might even last a lifetime.

Dr. Topalian reports a financial relationship with Bristol-Myers Squibb.

American Association for Cancer Research (AACR) 104th Annual Meeting. Presented April 7, 2013.

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