Breakthrough of the Year – Cancer Immunotherapy?

By Heather Lasseter, PhD, Medical Writer

Are advances in cancer immunotherapy a top scientific achievement of the year? 

Editors of Science certainly think so, heralding “cancer immunotherapy” as 2013’s Breakthrough of the Year: “This year marks a turning point in cancer, as long-sought efforts to unleash the immune system against tumors are paying off – even if the future remains a question mark.”

Awareness ribbons representing lung, breast, cervical, brain, kidney, prostate, and colon cancer, and melanoma (adapted from MesserWoland, wikimediacommons.org).

With June as Cancer Immunotherapy Month (designated by the Cancer Research Institute), cancer immunotherapy is a hot topic in oncology – especially as research here may lead to major treatment breakthroughs for many cancers. But currently approved treatment comes with a hefty price tag: approximately $120,000 for a round of therapy. Given the potentially modest impact on survival (for instance, on the order of several months), does cancer immunotherapy truly represent a key breakthrough of 2013?

 

Immune destruction – a hallmark of cancer

Hanahan and Weinberg’s hallmarks of cancer (Cell. 2011;144:646-674).

Avoiding immune destruction was recognized as one of the emerging hallmarks of cancer by Hanahan and Weinberg in 2011. Cancer cells survive and thrive through their well-known characteristics of ceaseless proliferation and invasion, as well as their ability to  evade the body’s natural defenses. While the immune system is tasked with cleaning up cells gone rogue, cancer cells not only escape these defense mechanisms, but hijack the immune system for their own advantage (i.e., tumor angiogenesis).

Cancer immunotherapy – the idea of targeting the body’s own immune system to attack cancerous cells – has been around for about 20 years. But with poor understanding of mechanisms for immune activation and hesitancy from pharmaceutical companies, cancer immunotherapy has only recently gained traction.

Early work by cancer immunologist James Allison (published in Science in 1996) sparked the renaissance in cancer immunotherapy. He demonstrated that administering antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4) in vivo caused the rejection of tumor cells. However, it was not until 15 years later that ipilimumab – a monoclonal antibody that targets CTLA-4 on T cells – became the first immunotherapy approved for treating metastatic melanoma. While cancer cells release antigens that activate the immune system, they also produce proteins that bind to CTLA-4, thereby preventing a full-out immune attack. Ipilimumab blocks this inhibitory signal, letting the immune system do its job. The result: cancer cell death.

Clinical trials are currently underway to assess efficacy of ipilimumab and other agents targeted to  reverse immune checkpoint pathways, which cancer cells exploit to inhibit the immune system. These are being assessed in the treatment of melanoma, lymphoma, lung, breast, gastric, and prostate cancers. Such agents include antibodies against programmed death-1 (PD-1), a molecule on T cells that puts the brakes on T-cell activation. Moreover, combination therapy of an anti-CTLA-4 plus anti-PD-1 has produced a “rapid and deep tumor regression” in patients with advanced melanoma, according to a study published in the New England Journal of Medicine. In addition, more recent advances involve genetically engineering T cells to express chimeric antigen receptors (CARs). CARs permit T cells to specifically target antigens on tumor cells.

One exciting possibility may be personalized immunotherapy

In a recent study in Science, CD4+ T helper cells were identified that responded to a mutated antigen found in the cancer cells of a patient with metastatic epithelial cancer. These mutation-reactive immune cells were extracted, amplified in cell cultures, and transfused back to the patient using a technique called adoptive cell transfer. The results were remarkable: the tumor regressed and then stabilized until 13 months post-transfusion. Following disease progression and a second round of immunotherapy, the tumor again regressed (last follow-up of 6 months).

Adoptive T-cell therapy (Simoncaulton, wikimediacommons.org).

Broadening the cancer immunotherapy pool

In the last several years, many groups have launched themselves into this line of research. As part of its Moon Shots Program, the University of Texas MD Anderson Cancer Center has collaborated in 2014 with four large companies – Johnson & Johnson, Pfizer, GlaxoSmithKline, and AstraZeneca’s MedImmune – to accelerate the development of immunotherapies and reduce cancer deaths. And cancer immunotherapy was a hot topic at the ASCO Annual Meeting, with large pharmaceutical companies sharing promising clinical data:

• Bristol-Myers Squibb: Combination of the PD-1 immune checkpoint inhibitor nivolumab plus ipilimumab in a phase 1b trial shrank tumors in 42% of patients with advanced melanoma and produced 1- and 2-year overall survival of 85% and 79%, respectively.
• Merck: In a phase 1b trial, the anti-PD-1 antibody pembrolizumab (MK-3475) reduced tumors in 51% of patients with PD-ligand 1 (PD-L1)-positive advanced head and neck cancer and produced a best overall response rate (ORR) of 20%.
• Roche: In a phase 1 trial, the anti-PD-L1 therapy MPDL3280A shrank tumors in 43% of patients with PD-L1-positive metastatic bladder cancer and produced an ORR of 52%.
• AstraZeneca: Although the clinical data were limited, AstraZeneca described the phase 1 dose-escalation trial assessing the PD-L1 inhibitor MEDI-4736 plus CTLA-4 inhibitor tremelimumab in patients with advanced solid tumors.

Moving cancer immunotherapy forward

While these results are promising, cancer immunotherapy only benefits a certain population of patients – and the reasons why are poorly understood. For instance, treatment efficacy may be impaired by the presence of mutations in a patient’s tumor that confer protection against antitumor immunity. As stated by Tjin et al in Cancer Immunology Research, “Immunotherapy is a promising strategy… but the modest clinical responses so far call for improvement of therapeutic efficacy.”

So what’s next for cancer immunotherapy?

It will be necessary to develop biomarkers for patients who will show a clinical benefit, increase the proportion who respond to treatment, and develop more potent treatment strategies. Treatment strategies will likely involve combination therapies, adding an immune system booster, and streamlining the development of targeted treatments. Progress to broaden and optimize the benefits of cancer immunotherapy is needed to make it worthy of being called the “Breakthrough of the Year.”