Cancer vaccines: renewed role in immuno-oncology combinations

Matthew Lehman of Prima BioMed explores the cancer vaccine space.

The field of immuno-oncology (I-O) has attracted tremendous scientific and investor interest as of late. This recent excitement in the I-O field has been driven primarily by advances in the understanding of immune checkpoints such as CTLA4, PD1, PDL1, CD137, OX40, and LAG3. This year has seen a number of large deals for preclinical checkpoint agents get done on terms typically reserved for clinical stage assets.

All this excitement is certainly warranted. Physicians have observed remarkable responses from early checkpoint inhibitor clinical trials. However, two issues are emerging that will be very important to the I-O field. First, only about one-third of patients seem to benefit from single agent treatment with a checkpoint inhibitor. Second, most of the products in clinical trials have important immune-related toxicity that will need to be better understood and managed.

"The field of immuno-oncology (I-O) has attracted tremendous scientific and investor interest as of late."

It is increasingly evident that future successful cancer treatment will involve I-O combinations to address these concerns and cancer vaccines figure to be a critical part of this mix.

Checkpoint inhibitors – "take out the enemy defenses"

Among the biggest challenges of successfully beating cancer has been the ability for cancer cells to mutate, evade the body's immune system, and regrow even after response to front line treatment.

Immune checkpoints appear to play a major role in the ability of cancer cells to hide from the immune system and they appear to generally suppress the immune response of a patient against malignancies. Ipilimumab, marketed as Yervoy® by Bristol-Myers Squibb, is the first checkpoint inhibitor to receive marketing approvals.

Though the checkpoint inhibitors have proven promising, a successful clinical response requires that patients are able to generate their own innate and adaptive immune response – i.e. the stimulation of NK or T and B cells that will target and kill the cancer cells. In about two-thirds of cases, it is not enough to just remove the cancer's defenses. We need an effective offense, too.

Co-stimulatory immune agents – "accelerate the immune system"

Co-stimulatory agents, such as those targeting OX40 and CD137, intended to accelerate immune response are receiving attention as potentially potent combinations with checkpoint inhibitors. But it has proven challenging to develop functional molecules against these targets, and there have been some significant concerns related to toxicity.

Several co-stimulatory product candidates have now made it into phase 1 clinical trials. This remains a key area of promise to help "rev up" the immune response to kill cancer cells.

"...most of the products in clinical trials have important immune-related toxicity that will need to be better understood and managed."

Cancer vaccines – "turn on the immune system"

Cancer vaccine ideas have been at the forefront of the I-O field for more than one hundred years. It appeared that Dendreon's launch of Provenge® in 2010 would open up the flood gates for large numbers of new cancer vaccines to enter the market.

However, reality has proven more challenging. Given the mechanism of action of cancer vaccines, scientists have precious few data points to help assess a cancer vaccine's potential without observing relatively large numbers of patients over extended periods of time. And, of course, there is the issue of cancer cell defenses – in many patients, cancer cells effectively mutate and regenerate and can hide from the immune system.

Nonetheless, it is clear that cancer vaccines can be very effective in stimulating cancer killing immune cells. Increasing evidence suggests that cancer vaccines will be particularly important in regenerating immune systems in patients who are compromised after surgery, radiation, or chemotherapy. Cancer vaccines "turn on" the engine that is the immune system and will likely play an important role in I-O combinations, working synergistically with checkpoint inhibitors, co-stimulatory agents, and even other non-immunological mechanisms.

Many cancer vaccines have made use of different vectors technologies to stimulate an antigen-directed T cell response such as bacteria, viruses, yeast, and even patients own white blood cells. The potential library of cancer antigens to apply to these vectors is large and well understood. So it will be exciting to see how these different technologies and antigens are put together as products and brought through development.

When talking about potential combinations with checkpoint inhibitors, Drew Pardoll, Director of the Cancer Immunology Program in Johns Hopkins University's Sidney Kimmel Comprehensive Cancer Center noted in a recent Nature Reviews article that "the real excitement lies with cancer vaccines. 'Their stock is very low right now, but they are going to come roaring back.'"

About the author:

Matthew Lehman is Chief Executive Officer of Prima BioMed, a biotechnology company developing personalized immunocellular cancer vaccines. Prima's lead program is a phase 2 trial of CVac™ for the treatment of epithelial ovarian cancer.

Prior to being appointed CEO in 2012, he was Prima's Chief Operating Officer since 2010. Mr. Lehman was previously Chief Operating Officer of a contract research organization for 10 years, where he grew a successful consulting practice advising investors and pharma industry clients on issues related to clinical trial design. He has organized teams to execute clinical trials for hundreds of products including successful pivotal trials of now marketed drugs such as Lyrica® and removab® for clients as diverse as large pharma and small biotech.

Mr. Lehman has a BA from the University of Louisville and MS from Columbia University.

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