Beyond PD-1: Harnessing Receptor Crosstalk to Overcome Immune Escape

Best Practices in Immunotherapy – June/July 2017 Vol 8

Immune checkpoint therapy, specifically PD-1 blockade, has improved survival for patients with metastatic cancer, but not all patients respond to treatment. At the 2017 ASCO-SITC Clinical Immuno-Oncology Symposium, Robert L. Ferris, MD, PhD, presented theoretical and practical ideas based on clinical and laboratory data about what to do with patients who eventually progress.

“Immune checkpoint blockade is therapeutically active in metastatic cancer, but we need to find a way forward in dealing with nonresponders,” said Dr Ferris, Associate Director for Translational Research; Co-Leader, Cancer Immunology Program; and Chief, Division of Head and Neck Surgery at the University of Pittsburgh Medical Center. “Cell extrinsic checkpoint inhibition or costimulation may provide additive or synergistic benefit over monotherapy and prevent resistance.”

“In addition, radiotherapy may be a good partner to reverse anti–PD-1 resistance, and we need to recognize metabolic changes,” Dr Ferris added. “On-treatment biopsies and/or imaging technology may help us with sequential dynamic biomarkers.”

Targeting PD-1 and CTLA-4

As Dr Ferris reported, cell intrinsic mechanisms of T-cell inhibition may be due to “crosstalk” between signaling pathways, but cell extrinsic mechanisms are just as important. The most obvious example of this is targeting both PD-1 and CTLA-4 receptors.

“We’ve begun to understand that PD-1–high regulatory T cells are different and targetable,” Dr Ferris explained. “As seen in subsets of melanoma and lung cancer patients, it’s clear that combining these negative regulatory signals with positive agonists is a promising strategy beyond anti­–PD-1 alone.”

However, not every patient benefits from dual targeting. According to Dr Ferris, on-treatment biopsies may help elucidate how these combination therapies are working beyond PD-1. It’s possible they’re depleting regulatory T cells or overcoming some inhibition on the effector T cell, he suggested.

Combining PD-1 with Lirilumab

Beyond anti–CTLA-4, one option is lirilumab, a fully human monoclonal antibody that blocks inhibitory killer cell immunoglobulin-like receptors (KIRs) on natural killer (NK) cells and promotes NK cell activation and tumor cell death. As Dr Ferris reported, there is rationale for combining lirilumab with nivolumab, a fully human monoclonal antibody that blocks PD-1 receptor inhibition of T cells.

“Nivolumab improves survival compared with standard therapy in patients with advanced squamous cell carcinoma of the head and neck [SCCHN], and these tumors have a high infiltration of NK cells and KIR gene expression,” he explained. “This suggests that KIR blockade with lirilumab may enhance antitumor activity of nivolumab in patients with SCCHN.”

In fact, preclinical models have shown that the addition of an anti-KIR monoclonal antibody potentiates the efficacy of an anti–PD-1 monoclonal antibody. Moreover, preliminary efficacy of lirilumab plus nivolumab in patients with SCCHN reveals “promising data” with “deep and durable responses,” said Dr Ferris. The response rate for patients on nivolumab monotherapy was approximately 13%, but when combined with lirilumab, which targets NK cells, the response rate jumped to 24%.

Costimulatory agonists may also boost response, said Dr Ferris. Nivolumab combined with urelumab, a CD137 agonist, has shown activity in melanoma and a “very small signal” in head and neck cancer and non–small cell lung cancer.

“We also observed a complete response in SCCHN,” said Dr Ferris, “but it was the only one. Clearly, there’s activity, though.”

Additional Combinations

In several disease states, immune checkpoint inhibitors are being combined with conventional therapies in addition to other immuno-oncology agents. In head and neck cancer, where cetuximab is used, for example, Dr Ferris noted several tumor-targeting antibodies, such as rituximab and trastuzumab, that may provide cell extrinsic crosstalk through cytotoxic antibody depletion and NK cell stimulation.

When NK cells were given an immunoglobulin G1 effector tumor-targeted antibody following a 4-week window with cetuximab, Dr Ferris and colleagues observed upregulation of CD137, suggesting that stimulation with an agonistic antibody would be useful.

“Combining 2 non-overlapping agents could create synergy,” said Dr Ferris. “This trial showed that by stimulating a cetuximab-activated NK cell, CD137 levels are enhanced in responders.”

“If you add lirilumab, you can enhance CD8 expression on dendritic cells, and NK cells survive better through the Bcl-2 pathway,” he added. “Sequential and on-treatment biopsy will allow us to put these combinations together.”

Boosting NK cells with a CD137 agonist is an important step, but investigators are also trying to overcome the cell extrinsic suppressive mechanisms in regulatory T cells. A study combining cetuximab with ipilimumab, an anti–CTLA-4 antibody, is attempting to do the latter, said Dr Ferris, who noted that initial clinical data have appeared quite promising.

Finally, there is preclinical rationale for combining anti–PD-1 therapy with TIM-3 blockade, which is also targeted in the clinic. Mouse models of head and neck cancer have shown that when tumor-infiltrating lymphocytes are blocked with anti–PD-1, TIM-3 expression is dramatically upregulated.

“When combined sequentially, anti–PD-1 and anti–TIM-3 can rescue some of the tumor progression by blocking TIM-3,” said Dr Ferris. “Early data have suggested there’s intracellular crosstalk.”

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Last modified: November 5, 2020

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