Despite the success of immunotherapies based on blocking the programmed cell death 1 (PD-1) receptor protein in metastatic melanoma patients, more than half do not experience a lasting benefit by seeing their tumors shrink. One possible reason the drug doesn’t work well for all patients is that these PD-1 blocking drugs lack a biological effect in many patients. However, new studies now indicate that 80 percent of these patients do, in fact, have an increase in the number of responding T cells to these types of treatments. The PD-1-targeting antibody pembrolizumab is a checkpoint inhibitor drug that takes the brake off the PD-1 receptor to allow T cells to replicate and react more strongly to cancer cells.

But why the considerable disconnect between shrinking tumors and ballooning T cell numbers in this patient population? A new study published in Nature provides clues that could enhance physicians’ ability to pinpoint, in real-time, which patients are not responding to therapy – and intervene with additional drugs to boost the chances of shrinking tumors. The paper is the first major publication to come out of the Parker Institute for Cancer Immunotherapy research collaborative.

“We found that the size of the pretreatment tumor determined how strong of a T cell response was needed in response to the drug to shrink a patient’s tumor,” said senior author E. John Wherry, PhD, a professor of Microbiology and co-director of the Parker Institute for Cancer Immunotherapy at the Perelman School of Medicine at the University of Pennsylvania. “The bigger the tumor, the more T cell ‘reinvigoration’ was needed by the drug. The ‘clinical failure’ that many patients experience was not solely due to an inability to spur the immune system, but rather resulted from an imbalance between the intensity of T-cell reinvigoration and initial tumor burden.”

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