clinical topic updates

Immunotherapy and Gastrointestinal Stromal Tumors

by Arun Singh, MD

Overview

Tyrosine kinase inhibitors (TKIs) for gastrointestinal stromal tumors (GIST) are effective; however, resistance typically develops. In addition to the development of novel biochemically designed TKIs, research focused on immunotherapy for GIST has shown promise, and this treatment is being investigated with and without concurrent TKI therapy.

Expert Commentary

Arun Singh, MD

Associate Professor
David Geffen School of Medicine
UCLA Medical Center
Santa Monica, CA

This is a rich area of ongoing research, both in the laboratory and in the clinic. There may be a role for immunotherapy in GIST, and we hope to have more definitive data in the coming years.”

Arun Singh, MD

GIST has traditionally been thought of as a disease that is driven by the tyrosine kinase receptors KIT and PDGFRA. For the most part, that pathophysiology is very sound, but there have always been indicators of more happening in the pathobiology. GIST cells arise in the context of a tumor microenvironment consisting of blood vessels, supporting cells, and immune cells. The immune cells include tumor-associated macrophages, T cells, and natural killer cells. While, certainly, there is a rich interplay going on, we do not fully understand all of the interactions that are occurring.

An increased understanding of the tumor microenvironment, together with preclinical findings in a mutant mouse model, have spurred the investigation of immunomodulating drugs or drug combinations in patients with GIST. DeMatteo and colleagues developed a GIST mutant mouse model. In these models, TKIs are very effective, but the effect is augmented with the addition of immunotherapy. In a trial investigating the CTLA-4–blocking drug ipilimumab plus a TKI, it was speculated that this combination would have synergistic or additive properties; however, the results of the study were disappointing. Another trial conducted by researchers in France examined the effects of cyclophosphamide used in combination with the PD-1 inhibitor pembrolizumab in 10 patients with GIST, but the combination showed only modest activity. Cyclophosphamide is an immunosuppressive drug, and it may have inhibited the activity of pembrolizumab in this study. There is also evidence suggesting that interferon gamma might be associated with a more sustained response to imatinib. The addition of interferon may help recruit effector cells into the tumor microenvironment, where they eradicate tumors.

In our own work here at the University of California, Los Angeles, we have used checkpoint blockers, including the PD-1 blocker nivolumab, in combination with ipilimumab in patients with GIST. We have shown that some patients with GIST experienced sustained benefits with either single-agent nivolumab or the combination. We have not seen much tumor shrinkage, but we have observed the inhibition of disease progression with this combination.

Thus, this is a rich area of ongoing research, both in the laboratory and in the clinic. There may be a role for immunotherapy in GIST, and we hope to have more definitive data in the coming years.

References

Blakely AM, Matoso A, Patil PA, et al. Role of immune microenvironment in gastrointestinal stromal tumours. Histopathology. 2018;72(3):405-413. doi:10.1111/his.13382

Indio V, Astolfi A, Urbini M, Nannini M, Pantaleo MA. Genetics and treatment of gastrointestinal stromal tumors with immune checkpoint inhibitors: what do we know? Pharmacogenomics. 2020;21(4):231-234. doi:10.2217/pgs-2019-0173

Kelly CM, Gutierrez Sainz L, Chi P. The management of metastatic GIST: current standard and investigational therapeutics. J Hematol Oncol. 2021;14(1):2. doi:10.1186/s13045-020-01026-6

Kondo J, Huh WJ, Franklin JL, Heinrich MC, Rubin BP, Coffey RJ. A smooth muscle-derived, Braf-driven mouse model of gastrointestinal stromal tumor (GIST): evidence for an alternative GIST cell-of-origin. J Pathol. 2020;252(4):441-450. doi:10.1002/path.5552

Mazzocca A, Napolitano A, Silletta M, Ceruso MS, et al. New frontiers in the medical management of gastrointestinal stromal tumors. Ther Adv Med Oncol. 2019;11:1758835919841946. doi:10.1177/1758835919841946

Ménard C, Blay J-Y, Borg C, et al. Natural killer cell IFN-gamma levels predict long-term survival with imatinib mesylate therapy in gastrointestinal stromal tumor-bearing patients. Cancer Res. 2009;69(8):3563-3569. doi:10.1158/0008-5472.CAN-08-3807

Pantaleo MA, Tarantino G, Agostinelli C, et al. Immune microenvironment profiling of gastrointestinal stromal tumors (GIST) shows gene expression patterns associated to immune checkpoint inhibitors response. Oncoimmunology. 2019;8(9):e1617588. doi:10.1080/2162402X.2019.1617588

Reilley MJ, Bailey A, Subbiah V, et al. Phase I clinical trial of combination imatinib and ipilimumab in patients with advanced malignancies. J Immunother Cancer. 2017;5:35. doi:10.1186/s40425-017-0238-1

Singh AS, Chmielowski B, Hecht R, et al. A randomized phase II study of nivolumab monotherapy versus nivolumab combined with ipilimumab in advanced gastrointestinal stromal tumor (GIST). J Clin Oncol. 2019;37(15 suppl):11017. doi:10.1200/JCO.2019.37.15_suppl.11017

Tan Y, Trent JC, Wilky BA, Kerr DA, Rosenberg AE. Current status of immunotherapy for gastrointestinal stromal tumor. Cancer Gene Ther. 2017;24(3):130-133. doi:10.1038/cgt.2016.58

Toulmonde M, Penel N, Adam J, et al. Use of PD-1 targeting, macrophage infiltration, and IDO pathway activation in sarcomas: a phase 2 clinical trial. JAMA Oncol. 2018;4(1):93-97. doi:10.1001/jamaoncol.2017.1617

Vallilas C, Sarantis P, Kyriazoglou A, et al. Gastrointestinal stromal tumors (GISTs): novel therapeutic strategies with immunotherapy and small molecules. Int J Mol Sci. 2021;22(2):493. doi:10.3390/ijms22020493

Zhang JQ, Bosbach B, Loo JK, et al. The V654A second-site KIT mutation increases tumor oncogenesis and STAT activation in a mouse model of gastrointestinal stromal tumor. Oncogene. 2020;39(49):7153-7165. doi:10.1038/s41388-020-01489-4

Zhang JQ, Zeng S, Vitiello GA, et al. Macrophages and CD8+ T cells mediate the antitumor efficacy of combined CD40 ligation and imatinib therapy in gastrointestinal stromal tumors. Cancer Immunol Res. 2018;6(4):434-447. doi:10.1158/2326-6066.CIR-17-0345

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