Upon further review: Immunotherapy’s curative potential

Immunotherapy is complex, has curative potential for some patients when given alone or combined with other drugs, and needs further support to more efficiently exploit its possibilities for cancer patients.

Those messages from two leaders in the field were delivered in a pair of reviews published recently in the prestigious scientific journals Cell and Science.

Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology and Immunology, and James Allison, Ph.D., chair of Immunology, co-wrote both reviews to highlight the curative potential of cancer immunotherapy and what needs to be done to advance the field.

Allison pioneered immune checkpoint blockade, an approach that treats the immune system rather than the tumor directly, blocking molecules on T cells that shut down those attack cells and protect tumors from immune response.

The intriguing aspect of checkpoint blockade is that while many patients don’t respond, a significant fraction that do have powerful, durable responses against their advanced disease.

Long-term follow-up of ipilimumab (Yervoy), an antibody developed out of Allison’s basic science research, found that 22% of late-stage melanoma patients treated have survived for at least four years, unprecedented results for the disease. Patients who survived three years have gone on to live up to 10 years and more.

The reviews address key issues in successfully extending these long-term remissions and cures to more patients with more types of cancer.

Immune response vs. targeted therapy

Genomically targeted therapies that hit specific targets on cancer cells often shrink tumors; however, the cancer typically becomes resistant to the drug because it can rely on other genomic drivers to thrive.

The immune system is designed to deal with the problem of genomic diversity of tumors, Allison said, as evidenced by the long-term survival of that fraction of melanoma patients.

“T cells are specific. They recognize and attack tumor-specific antigens down to the peptide level. They remember those target antigens forever, so they can thwart recurrence,” Allison said. “And T cell response is adaptable, generating custom T cells to match multiple targets found in the genomic diversity of the tumor or generated by new mutations.”

So checkpoint blockade should logically work for more patients. “We need to understand why some patients don't respond to immunotherapy,” Allison said.

First monitor immune response

In the Science review, Sharma and Allison discuss how monitoring immune response before, during and after treatment will help guide treatment and development of combination therapies.

“Identifying in advance who will benefit from treatment and developing combination therapies to improve and expand on current results will require us to decipher the dynamics of human immune response to tumors and their surrounding microenvironment,” said Sharma.

The goal should be to develop biomarker panels to help cultivate combination therapies and then examine tumor tissues for changes in those biomarkers in order to increase treatment impact.

“We know the constantly evolving nature of immune responses make it highly unlikely that a single biomarker could predict a patient’s response to one of these drugs,” Allison said.

Allison is executive director and Sharma scientific director of the immunotherapy platform for MD Anderson’s Moon Shots Program, which is designed to accelerate the conversion of scientific discoveries into clinical advances that significantly reduce cancer deaths. The platform has conducted immune monitoring analysis of tumor tissues in more than 50 MD Anderson clinical trials in the past two years.

Examine targeted therapy/checkpoint blockade combinations

The Cell review, titled “Immune Checkpoint Targeting in Cancer Therapy: Toward Combination Strategies with Curative Potential,” covers the strengths and weaknesses of the two forms of therapy and notes how their combination could be particularly potent.

Targeted therapies might act as effective cancer vaccines, killing tumor cells and releasing new target antigens for T cells to identify and associate with tumors. And they might vary in their ability to enhance or inhibit immune response, because little is known right now about how targeted agents affect the immune system, Sharma said. Additional research is needed in this area.

Special care must be taken with combinations, because “the more therapies you put together, the more toxicities you have to face” that cause side effects, Sharma notes. Differences in drugs, doses and dosing schedule need to be evaluated.

Other immunotherapies that block additional T cell checkpoints or that stimulate immune response are newly approved or in development. Add those to existing targeted therapies and other treatments, and there’s a multitude of possible combinations. More effective preclinical research could make choosing of combinations worthy of clinical trials more precise.

Enhanced support for immunotherapy

Sharma and Allison close by noting that federal funding for cancer research has been “overwhelmingly directed toward genomically targeted therapies.”

They conclude: “At this stage, it does not seem a stretch to say that increasing funding to combination therapies will be key to development of new, safe treatments that may prove to be curative for many patients with many types of cancer.”