TAM kinase inhibition and immune checkpoint blockade– a winning combination in cancer treatment?

ABSTRACT

Introduction: Immune checkpoint inhibitors (ICI) have shown great promise in a wide spectrum of malignancies. However, responses are not always durable, and this mode of treatment is only effective in a subset of patients. As such, there exists an unmet need for novel approaches to bolster ICI efficacy.

Areas covered: We review the role of the Tyro3, Axl, and Mer (TAM) receptor tyrosine kinases in promoting tumor-induced immune suppression and discuss the benefits that may be derived from combining ICI with TAM kinase-targeted tyrosine kinase inhibitors. We searched the MEDLINE Public Library of Medicine (PubMed) and EMBASE databases and referred to ClinicalTrials.gov for relevant ongoing studies.

Expert opinion: Targeting of TAM kinases may improve the efficacy of immune checkpoint blockade. However, it remains to be determined whether this effect will be better achieved by the selective targeting of each TAM receptor, depending on the context, or by multi-receptor TAM inhibitors. Triple inhibition of all TAM receptors is more likely to be associated with an increased risk for adverse events. Clinical trial designs should use high-resolution clinical endpoints and proper control arms to determine the synergistic effects of combining TAM inhibition with immune checkpoint blockade.

KEYWORDS:

• TAM kinase inhibitors
• immune checkpoint inhibitors
• cabozantinib
• sitravatinib
• combination therapy

Article highlights

• Tyro3, Axl, and Mer (TAM) receptor tyrosine kinases play key roles in oncogenesis

• TAM kinases may downregulate innate immunity and cause immune suppression in cancer

• Multiple receptor tyrosine kinase inhibitors (TKIs) against TAM receptors may synergize with immune checkpoint blockade

• The combination of TAM inhibitors with immune checkpoint inhibitors is being actively investigated in clinical trials

• The TAM receptor TKIs currently furthest along in clinical development are cabozantinib and sitravatinib

This box summarizes key points contained in the article.

Acknowledgments

Medical writing and editorial assistance were provided by Joanne Franklin, PhD, CMPP, Aptitude Health, The Hague, the Netherlands, funded by Exelixis.

Declaration of interest

P Msaouel Has received honoraria for service on a Scientific Advisory Board for Mirati Therapeutics, Exelixis, and BMS, consulting for Axiom Healthcare Strategies, non-branded educational programs supported by Exelixis and Pfizer, and research funding for clinical trials from Takeda, BMS, Mirati Therapeutics, Gateway for Cancer Research, and UT MD Anderson Cancer Center. J Gao serves as a consultant for ARMO Biosciences, AstraZeneca, CRISPR Therapeutics, Jounce, Nektar Therapeutics, Pfizer, Polaris, and Symphogen.

NM Tannir has received honoraria for service on Scientific Advisory Boards for Bristol-Myers Squibb, Eli Lilly and Company, Exelixis, Inc. and Nektar Therapeutics, for strategic council meeting with Eisai Inc., steering committee meeting with Pfizer, Inc. and for seminar presentations for Ono Pharmaceutical CO., Ltd., as well as research funding for clinical trials from Exelixis, Inc., Calithera Biosciences, and Nektar Therapeutics. S Sen is an Exelixis employee and owns shares in the company. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer was involved in drug development of TAM receptor small molecule inhibitors and is a co-founder of Meryx, a startup company with a TAM inhibitor in Phase I clinical trials. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by Exelixis.