A review, titled Immune Checkpoint Targeting in Cancer Therapy: Toward Combination Strategies with Curative Potential, from researchers at The University of Texas MD Anderson Cancer Center published in Cell, covers the strengths and weaknesses of the two forms of therapy ( genomically targeted therapy and immune checkpoint blockade ) and notes how their combination could be particularly potent.
Targeted therapy: frequent but short-lived responses
The molecular mechanisms involved in the development of cancer have been uncovered by extensive research over the past 30 years, culminating in The Cancer Genome Atlas, a National Institutes of Health project that identified and characterized many genetic mutations that fuel cancer.
Drugs that hit a specific genomic defect that drives a patient’s cancer provoke good initial responses in most patients. For example, drugs that target a specific BRAF gene mutation commonly found in melanoma shrink tumors in about half of patients with the mutation.
However, resistance almost always develops because tumors harbor multiple genomic defects capable of driving the disease after a targeted drug knocks down one driver. BRAF inhibitors prolonged median survival in clinical trials by about seven months.
Checkpoint blockade: fewer but stronger results
Immune checkpoint blockade is an approach that treats the immune system, rather than the tumor directly, by blocking molecules on T cells that shut those attack cells down, protecting tumors from immune response.
The first such drug, called Ipilimumab ( Yervoy ) showed much lower response rates against advanced melanoma than those obtained with targeted drugs, but long-term follow-up found that 22% of those treated with Yervoy survived at least four years, unprecedented results for the disease. Importantly, those who survived three years have gone on to live up to 10 years and beyond.
Drugs that hit other immune checkpoints have been developed after Yervoy and show similar response rates in a variety of cancers.
Immunity is key to long-term responses
Knowing that the immune system is capable of recognizing distinctive features of cancer cells and launching a T cell attack against those tumor antigens, and that checkpoint blockade removes a roadblock to that attack, it’s logical that these drugs should work against many tumor types. But the impact varies across cancers.
Researchers need to understand why some patients don't respond to immunotherapy, but in others, the response is dramatic, as evidenced by the long-term survival of the those melanoma patients.
How combinations might work
Combining multiple genomically targeted therapies might prove effective. However, evidence suggests that tumor genomic diversity might still defeat such combinations, and that it’s axiomatic in oncology that side effects increase in number and intensity as more drugs are added to treatment.
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.
Early efforts to combine approaches have yielded interesting results. One phase I trial of an immune checkpoint blockade drug combined with two established targeted therapies yielded 40-50% response rates among patients with metastatic kidney cancer. Follow-up has not been long enough to determine durability of responses or impact on survival.
Two clinical trials combining Yervoy with two different BRAF inhibitors in melanoma illustrate potential issues for combination therapy. In one case, liver toxicity led to closure of the trial, while the other combination appears well-tolerated as the trial continues.
This highlights that differences in drugs, doses and dosing schedule need to be evaluated as physicians develop combination therapies.
While checkpoint blockade drugs currently focus on blocking two checkpoint mechanisms, others have been identified by research, as well as molecules that stimulate immune response. These provide new targets for immunotherapy. Facing multitudes of possible drug combinations, more effective preclinical research could make the choosing of such combinations for clinical trials more precise. ( Xagena )
Source: University of Texas MD Anderson Cancer, 2015