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Review
. 2022 May 26;11(1):2077898.
doi: 10.1080/2162402X.2022.2077898. eCollection 2022.

Trial Watch: combination of tyrosine kinase inhibitors (TKIs) and immunotherapy

Adriana Petrazzuolo  1   2 , M Chiara Maiuri  1   2 , Laurence Zitvogel  3   4   5   6 , Guido Kroemer  1   2   7 , Oliver Kepp  1   2
Affiliations
Review

Trial Watch: combination of tyrosine kinase inhibitors (TKIs) and immunotherapy

Adriana Petrazzuolo et al. Oncoimmunology. .

Abstract

The past decades witnessed the clinical employment of targeted therapies including but not limited to tyrosine kinase inhibitors (TKIs) that restrain a broad variety of pro-tumorigenic signals. TKIs can be categorized into (i) agents that directly target cancer cells, (ii) normalize angiogenesis or (iii) affect cells of the hematologic lineage. However, a clear distinction of TKIs based on this definition is limited by the fact that many TKIs designed to inhibit cancer cells have also effects on immune cells that are being discovered. Additionally, TKIs originally designed to target hematological cancers exhibit bioactivities on healthy cells of the same hematological lineage. TKIs have been described to improve immune recognition and cancer immunosurveillance, providing the scientific basis to combine TKIs with immunotherapy. Indeed, combination of TKIs with immunotherapy showed synergistic effects in preclinical models and clinical trials and some combinations of TKIs normalizing angiogenesis with immune checkpoint blocking antibodies have already been approved by the FDA for cancer therapy. However, the identification of appropriate drug combinations as well as optimal dosing and scheduling needs to be improved in order to obtain tangible progress in cancer care. This Trial Watch summarizes active clinical trials combining TKIs with various immunotherapeutic strategies to treat cancer patients.

Keywords: Immunotherapy; checkpoint blockade; lung cancer; personalized medicine; targeted therapy.

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Conflict of interest statement

OK is a scientific co-founder of Samsara. GK has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Samsara, Sanofi, Sotio, Tollys, Vascage and Vasculox/Tioma. GK has been consulting for Reithera. GK is on the Board of Directors of the Bristol Myers Squibb Foundation France. GK is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. GK is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis and metabolic disorders. MCM is named as an inventor on a patent describing a method for the diagnosis and prognosis of breast cancer.

Figures

Figure 1.
Figure 1.
Functional TKI categories. Tyrosine kinase inhibitors (TKIs) can be functionally categorized into agents with cytotoxic or cytostatic effects on cancer cells leading to the establishment of chemokine gradients and improving the elimination of tumors by CD8+ cytotoxic T lymphocytes (CTLs) (A). TKIs from the second category are endowed with angiogenesis normalizing effects and favor immune cell migration toward tumors (B). The third category of TKIs encompasses inhibitors originally developed to target hematological cancers that have been found to also activate immune cells such as dendritic cells and CTLs (C).
Figure 2.
Figure 2.
Heatmap of TKI combination with immunotherapy.The heatmap shows the number of clinical trials combining FDA-approved tyrosine kinase inhibitors (TKIs) with immunotherapies grouped according to their mechanism of action.
See this image and copyright information in PMC

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