Targeted Checkpoint Blocking Therapies Not Yet an Effective Melanoma Treatment, Cancer Expert Says

Targeted Checkpoint Blocking Therapies Not Yet an Effective Melanoma Treatment, Cancer Expert Says

In a talk at the recent HemOnc Today’s Melanoma and Cutaneous Malignancies meeting, Christian Blank, group leader of the division of immunology at Netherlands Cancer Institute, presented his views of checkpoint blocking therapies. He concluded that targeted therapy is not enough to fight melanoma.

Checkpoint blocking therapies, such as anti-PD1 and anti-CTLA4, had given many late-stage melanoma patients new hope. It was believed that targeted therapy, based on the presence of certain molecules in cancer patients, would allow clinicians to choose therapies directed at these specific molecules. Studies have, however, shown that the beneficial effects are short, and checkpoint inhibition might be more complex than scientists realized.

Researchers currently believe that high levels of PD1 in a patient are indicative of treatment response, and can be viewed as a biomarker. During his March 18 talk, Dr. Blank criticized this idea, suggesting that the expression of PD1 and similar molecules is a highly dynamic affair, responsive to environmental changes such as other treatments. In his opinion, a tissue biopsy showing low levels of PD1 at one point in time is not necessarily linked to a lack of treatment response.

According to Dr. Blank, there is no question that checkpoint blocking therapies will form the backbone of melanoma treatment. But in his experience, he said, immunotherapies help more patients than targeted therapies, and combining these therapies is likely the way to go forward.

“We have treated a lot of patients with immunotherapy, and also a lot of patients with targeted therapy, and the number of patients having long-term benefits, allowing them to stop the treatment, I can count on my fingers,” he said, referring to findings of a lack of long-term benefits for melanoma patients on targeted therapies.

Nevertheless, Dr. Blank believes there is much more to gain from checkpoint blocking therapy than is currently understood. He referred to checkpoint modulation as an orchestra of stimulatory and inhibitory signals, mentioning an array of factors that are critical in checkpoint inhibition.

He went on to present preclinical data showing how the blockade of three of these factors — LAG-3, TIM-3, CD137 — had one thing in common: a synergistic effect when given together with anti-PD1 checkpoint blockers, inhibiting tumor growth more than could be expected.

According to Dr. Blank, this indicates these molecules are part of the same pathway but function in a hierarchical manner, with PD1 being the most important factor. Moreover, treatment with the combined PD1 and CD137 checkpoint blockers successfully slowed tumor growth in a mouse model not considered susceptible to checkpoint inhibition.

These three new checkpoint inhibitors, along with an array of other factors, have now reached Phase 1 clinical trials.

Dr. Blank also raised the issue of how to address the endless combination of possibilities presented by the cascade of checkpoint inhibitors and surface molecules of individual cancer patients. Currently, all available options are often used at once, raising the risk of potential toxicity. More rational ways of using checkpoint blocking therapies exist, he concluded.

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