Semaphorin 4D (SEMA4D, and its receptor, plexin B1) is broadly expressed in malignant tumors. Aside from other “normal functions” in tumors, SEMA4D influences the infiltration and distribution of leukocytes into the microenvironment, and its inhibition promotes functional immune infiltration. “SEMA4D inhibition, therefore, is a rational way of halting tumor progression,” according to Timothy A. Yap, MBBS, PhD, FRCP, Associate Professor in the Department of Investigational Cancer Therapeutics (Phase I Program), and Medical Director of the Institute for Applied Cancer Science at The University of Texas MD Anderson Cancer Center, Houston.
Timothy A. Yap, MBBS, PhD, FRCP
Dr. Yap commented on the “striking” preclinical results presented by Dr. Ruffolo, showing the longest survival to be with FOLFIRINOX (leucovorin, fluorouracil, irinotecan, oxaliplatin), double checkpoint blockade, and anti-SEMA4D therapy compared to other combinations. “It’s certainly very impressive,” he said, adding that the doubling of penetration by CD8-positive effector T cells within tumors vs controls, after treatment with SEMA4D plus checkpoint blockade, was preclinical proof of concept for the mechanism.
“Overall, this provides clear rationale and supporting evidence to proceed to the clinic, especially where there is an urgent unmet clinical need, such as pancreatic cancer,” he commented.
Dr. Yap predicted that the forthcoming clinical trial combining FOLFIRINOX, checkpoint blockade, and SEMA4D therapy, because of its rational and staged design, will yield “a clear go/no-go decision based on early signals of activity observed in the initial groups of patients treated.”
He further saw proof of mechanism of this approach in Dr. Shafique’s study of pepinemab plus avelumab in advanced non–small cell lung cancer (NSCLC), where this regimen increased CD8-positive T-cell infiltration and provided clinical benefit in 81% of immunotherapy-naive patients and 59% of those pretreated with checkpoint inhibitors.
“The key question is whether this is an active combination in NSCLC. In my opinion, it is, but is it going to be enough to take it past registration?” he questioned. Dr. Yap suggested that the investigators test this combination further in programmed cell death ligand 1 (PD-L1)-low or PD-L1–null immunotherapy-resistant patients, which has shown preliminary antitumor activity in this trial and is a current area of unmet need. Other potential clinical lines of sight include exploring the antitumor activity of this combination in other cancer types, and to consider combinations with chemotherapy or other novel agents.
“All of this really begs the key question: are empirical combinations really the solution to all of our challenges with immunotherapy?” Dr. Yap further asked. “Our current paradigm of just adding something to an existing therapy may not be correct…. Biology should ultimately be driving the development of our strategies.”
DISCLOSURE: Dr. Yap has served in a consulting or advisory role for Aduro Biotech, Almac, AstraZeneca, Atrin Pharmaceuticals, Bayer, Bristol-Myers Squibb, Calithera Biosciences, Clovis Oncology, Cybrexa, EMD Serono, Ignyta, I-Mab, Janssen, Merck, Pfizer, Roche, Seattle Genetics, Tesaro, Vertex, and Zai Laboratories; has received research funding from AstraZeneca, Bayer, Constellation Pharmaceuticals, Jounce Therapeutics, Kyowa Hakko Kirin, Lilly, Pfizer, Seattle Genetics, Tesaro, and Vertex; has an intellectual property interest in an institutional patent, “IACS-010759”; and has been reimbursed for travel, accommodations, or other expenses by Atrin Pharmaceuticals, Calithera Biosciences, Eli Lilly, EMD Serono, Pfizer, and Tesaro.
A novel class of inhibitors may hold some promise for boosting responses to checkpoint inhibitors and for sensitizing poorly immunogenic tumors, such as pancreatic cancer, to immunotherapy. The drug targets semaphorin 4D (SEMA4D), a glycoprotein expressed on the cell membranes of many tumor types....