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High Expression of Alternative Checkpoints, CD68 Associated With Resistance to Anti-PD1 Therapy

NEW YORK – Researchers in the US and Japan have found that the overexpression of certain biomarkers associated with the cancer-immunity cycle in the pan-cancer setting was significantly associated with shorter progression-free survival (PFS) after anti-PD1/PD-L1-based therapies.

The study of cancer immunity biomarkers recently published in the journal OncoImmunology also revealed complex immune profiles for most tumors, suggesting the need for customized combinations of immunotherapies.

Researchers led by Shumei Kato from the Moores Cancer Center at the University of California, San Diego described their analysis of 51 markers of the cancer-immunity cycle in 101 patients with diverse malignancies. The most common diagnosis was gastrointestinal cancer followed by gynecologic cancers. Among the 101 patients, 39 patients received anti-PD1/PD-L1 based regimens.

Overall, the researchers found that multiple receptors involved in mediating immune responses to cancer were overexpressed in patients, including VISTA, PD-L2, TIM3, LAG3, PD-L1, and CTLA4. They also observed aberrant expression of macrophage-associated markers such as CD68 and CSF1R, metabolic immune escape markers such as ADORA2A and IDO1, and T-cell priming markers such as CD40, GITR, ICOS and OX40.

About 87 percent of the tumors expressed distinct immune profiles. "This observation is comparable to that reported in the cancer genomic field where the landscape of genomic alterations is complex and differs between patients even when they harbor tumors of the same histologic diagnosis," the researchers wrote.

The investigators also found a median of six biomarkers that they described as "theoretically actionable," because they could be targeted by US Food and Drug Administration-approved agents, whether administered on- or off-label, or with agents in clinical development. Overall, 53 of the 101 patients had at least one theoretically actionable cancer-immunity cycle associated biomarker, and another 47 of the 101 patients had at least one cancer-immunity biomarker, which was potentially targetable with an agent that is in clinical investigation.

Importantly, the researchers found that overexpression of TIM-3, VISTA, and CD68 were significantly associated with shorter PFS in cancer patients after they received anti-PD1/PD-L1-based therapies.

Among the 39 patients who received anti-PD1/PD-L1 based immunotherapy, 32 patients were evaluable for response. The researchers found that high expression of TIM3 and VISTA was associated with lower rates of clinical benefit — defined as stable disease for six months or more, partial response, or complete response — in these patients. The five patients with very high or high levels of these biomarkers achieved no clinical benefit, whereas 14 out of the 27 patients with moderate, low, or very low levels of these biomarkers achieved clinical benefit.

The four patients expressing high levels of CD68 likewise achieved no clinical benefit from anti-PD1 treatment, whereas 14 of the 28 patients with moderate or low levels of that biomarker achieved some benefit.

The researchers did acknowledge that the small number of patients evaluable for response may have limited the power of the analysis.

TIM-3 is a cell surface receptor expressed on activated T cells, and TIM-3 upregulation is associated with resistance to anti-PD1 therapies in preclinical models. VISTA is an immunoregulatory receptor that inhibits T-cell activation, and its upregulation has been observed in patients with prostate cancer treated with ipilimumab (Bristol-Myers Squibb's Yervoy), suggesting a compensatory inhibitor pathway as a resistance mechanism after ipilimumab therapy, the researchers noted. Increased expression of VISTA has also been seen among melanoma patients who have progressed on anti-PD1 inhibitor therapy, suggesting a role for VISTA as an immune checkpoint.

"Since TIM-3 and VISTA were both implicated as resistant markers for anti-PD1/PD-L1-based immunotherapy in our dataset, targeting of TIM-3 and VISTA may be required to achieve a better clinical outcome in selected patients," the authors wrote.

They further noted that CD68 is a tumor-associated macrophage (TAM) marker, and that high TAM has been found to correlate with poor prognosis in breast cancer and myxoid liposarcoma patients. "In the preclinical setting, TAM has been reported to play a key role in resistance to anti-PD-1 therapy, which is in line with our current clinical observations," the researchers added.