A combination of experimental drugs increased the attack of immune cells on non-small cell lung cancer (NSCLC) to extend survival in mice, a new study found.
Led by researchers at NYU Grossman School of Medicine and its Laura and Isaac Perlmutter Cancer Center, the study results revolve around the immune system, and specifically T cells, which can destroy cells infected with foreign organisms like viruses. The immune system also recognizes cancer cells as abnormal, but tumors produce proteins that turn down immune responses, while immunotherapies seek to counter immune suppression and enhance T cell assault.
Published online August 5 in Cancer Discovery, the new study focused on the effect of a compound called SHP099, which blocks the action of SHP2, an enzyme that plays a critical role in pathways abnormally activated in specific cancer types. Although SHP099 is a “tool compound” that itself cannot be used in patients, several SHP2 inhibitors are in clinical trials for a variety of cancers.
The action of SHP2 is required for efficient activation of KRAS—a molecular switch that becomes “stuck in growth mode” to cause cancerous growth. In the current study, SHP099 treatment of mouse lung tumors caused by a mutant KRAS prevented them from growing; during the same time period; untreated tumors increased in size by 150 percent. These findings showed that at least some T cells in these mice were capable of killing tumor cells. Their effects were limited, however, as the tumors ultimately regrew and killed the mice, which led the study authors to suspect that another cell population might be interfering with T cell action.
The researchers then found that, in addition to its beneficial effects, SHP2 inhibition also causes an influx of granulocytic myeloid-derived suppressor cells (gMDSCs) into tumors, which signal T cells to switch into a type that does not attack tumors well. Subsequent experiments showed that SHP2 inhibition with SHP099 caused cancer cells to produce specific “chemokines,” signaling molecules that attract cells to the source of production, in this case, tumor cells. The chemokine produced upon SHP099 treatment function by binding a surface protein (receptor) on gMDSCs called CXCR2. The infiltrating gMDSCs then impaired the anti-tumor actions of T cells.
To overcome this inhibition, the researchers then tried combining SHP099 with a CXCR2 inhibitor, SX682, designed by Syntrix Pharmaceuticals and currently in clinical trials. This combination significantly reduced gMDSC infiltration compared with SHP099 alone and completely suppressed tumor growth after two weeks of treatment, the time point at which tumor-bearing mice treated with an inert molecule (vehicle) for comparison started to die. The combination also prolonged the survival (median: 38 days) as compared to SHP099 alone (median: 27 days) or just SX682 (median: 21.5 days), and more than doubled overall survival compared with vehicle-treated (median: 18 days) mice. The team found no toxicity after five weeks of combination treatment.
“Our study results showed how one targeted drug could address a weakness in the other, creating a stronger anti-cancer immune environment around tumors,” says co-corresponding author Kwan Ho Tang, PhD, a research scientist in the laboratory of Benjamin G. Neel, MD, PhD, director of Perlmutter Cancer Center. “We would argue that this combination should be tried together in a clinical trial.”
Experiments by the team confirmed that SHP2 inhibition itself causes an influx into tumors of gMDSCs, which are part of normal immune defenses but are changed by signals given off by tumors. The abundance of the gMDSCs in patients with cancer have been linked by past studies to reduced overall survival in multiple solid tumor types.
“We also found in experiments in human NSCLC cells that the influx of gMDSCs brought about by SHP2 inhibitors through CXCR2 may be sabotaging the ability of other emerging drug classes to harness T cell attack as well,” says co-corresponding author Kwok-Kin Wong, MD, PhD, the Anne Murnick Cogan and David H. Cogan Professor of Oncology in the Department of Medicine at NYU Langone Health and director of the Division of Hematology and Medical Oncology. “These may include MEK inhibitors, a newly FDA-approved drug designed to interfere with a single cancer-causing mutant protein called G12C present in many lung cancers, as well as EGF receptor inhibitors, an important treatment for patients with lung tumors carrying mutations in the EGFR gene.”
Finally, say the authors, the study suggests that additional “immune checkpoint” inhibitors could be added to the study combination in future examinations. The immune system uses “checkpoints”—sensors on immune cells that turn them off when they receive the right signal—to spare normal cells from immune attack. Cancer cells hijack checkpoints to turn off immune responses.
Along with Dr. Tang and Dr. Wong, the study was led by co-corresponding author Dr. Neel, and by first author Shuai Li. Other NYU Langone study authors are Jayu Jen, Han, Kayla Guidry, and Ting Chen at Perlmutter Cancer Center; Cynthia Loomis in the Department of Pathology; and Aristotelis Tsirigos, Alireza Khodadadi-Jamayran, and Yuan Hao in the Applied Bioinformatics Laboratories. Other study co-investigators are John Zebala and Dean Maeda of Syntrix Pharmaceuticals; James Christensen and Peter Olson of Mirati Therapeutics; Argus Athanas of Monoceros Biosystems, Inc.; and Carmine Fedele of the Novartis Institutes for BioMedical Research. The study was funded by National Institutes of Health grants P01CA229086, R01CA252239, CA49152, CA248896, and P30 CA016087.
Dr. Wong holds equity in G1 Therapeutics and Recursion Pharmaceuticals; has sponsored research agreements with Mirati Therapeutics, Takeda, BMS, Merus, Alkermes, Ansun Biopharma, Tvardi Therapeutics, Delfi Diagnostics, and Dracen Pharmaceuticals; and has consulting agreements with Allorion, AstraZeneca, Genocea, Epiphanes, Hillstream, Novartis, Merck, Recursion, Navire, Mirati, Prelude, Ono, Janssen, Pfizer, and Zentalis. Dr. Neel holds equity in, and receives consulting fees from, Navire Pharma and Jengu Therapeutics, and holds equity in Northern Biologics, Arvinas, and Recursion. He also has a sponsored research agreement with Mirati and received consulting fees from MPM Capital and Gerson Lehrman Group. His spouse holds equity in Amgen and held equity in Moderna and Regeneron at times during the current study. These relationships are being managed in keeping with the policies of NYU Langone.