Enhancing therapeutic anti-cancer responses by combining immune checkpoint and tyrosine kinase inhibition

Abstract

Over the past decade, immune checkpoint inhibitor (ICI) therapy has been established as the standard of care for many types of cancer, but the strategies employed have continued to evolve. Recently, much clinical focus has been on combining targeted therapies with ICI for the purpose of manipulating the immune setpoint. The latter concept describes the equilibrium between factors that promote and those that suppress anti-cancer immunity. Besides tumor mutational load and other cancer cell-intrinsic determinants, the immune setpoint is also governed by the cells of the tumor microenvironment and how they are coerced by cancer cells to support the survival and growth of the tumor. These regulatory mechanisms provide therapeutic opportunities to intervene and reduce immune suppression via application of small molecule inhibitors and antibody-based therapies against (receptor) tyrosine kinases and thereby improve the response to ICIs. This article reviews how tyrosine kinase signaling in the tumor microenvironment can promote immune suppression and highlights how therapeutic strategies directed against specific tyrosine kinases can be used to lower the immune setpoint and elicit more effective anti-tumor immunity.

Distant antimetastatic effect of enterotropic colon cancer–derived α4β7 + CD8 + T cells

“…In line with this postulate, high expression of the ITGB7 gene in tumors was associated with response to therapy and survival in patients with lung and urothelial cancer receiving ICB (49). Although multiple factors, including tumor mutational burden and association with tyrosine kinase signaling (54,55), are known to influence the immunogenicity of the tumor, our data suggest that, once initiated in the colon, the immune response can influence distant metastases. Although ICB showed minimal efficacy in mCRC (56), biomarkers predicting tumor response to ICB, in both patients with microsatellite instability (MSI) and MSS mCRC, are currently being sought (57).…”

Magnetic Metal–Organic Framework-Based Nanoplatform with Platelet Membrane Coating as a Synergistic Programmed Cell Death Protein 1 Inhibitor against Hepatocellular Carcinoma

“…It is considered one of the most challenging cancer types with poor prognosis. − Although surgery, radiotherapy, and chemotherapy are common curative approaches for HCC in clinical settings, their efficacy remains unsatisfactory; furthermore, they have notable side effects. − Recently, immune-checkpoint inhibitor (ICI)-based tumor immunotherapy has demonstrated promising efficacy in early phase trials; , in addition, it has exhibited superior safety in patients with HCC. − Programmed cell death protein 1 (PD-1) inhibitors, the most common ICIs, is considered a promising treatment approach for HCC. ,− PD-1 inhibitors can reactivate the antitumor function of tumor-infiltrating T lymphocytes (TILs) by inhibiting the interaction between programmed death-ligand 1 and PD-1 . However, in clinical settings, the objective response rate of PD-1 inhibitors is only 15%–20%. , Therefore, improving the antitumor effect of PD-1 inhibitors is an urgent but challenging task for HCC treatment. , …”

Discovery of a Novel Benzodiazepine Series of Cbl-b Inhibitors for the Enhancement of Antitumor Immunity

“…As such, evidence for T-cell activation through functional inhibition of Cbl-b has been shown in knockout (KO) mouse models, demonstrating that genetic deletion of Cbl-b resulted in hyperactive T-cells and inhibition of tumor growth . Therefore, discovery of small molecule inhibitors of Cbl-b could offer an alternative mechanistic approach to cancer immunotherapy, which could potentially treat patient populations that are nonresponsive to ICI therapies. , In addition, combination of a Cbl-b inhibitor with an ICI could have potential in overcoming resistance mechanisms, which would improve the standard of care for certain types of cancers …”

“…19 Therefore, discovery of small molecule inhibitors of Cbl-b could offer an alternative mechanistic approach to cancer immunotherapy, which could potentially treat patient populations that are nonresponsive to ICI therapies. 20,21 In addition, combination of a Cbl-b inhibitor with an ICI could have potential in overcoming resistance mechanisms, which would improve the standard of care for certain types of cancers. 20 Cbl-b, like other members of the Cbl family, contains all of the structural features required for E3 ubiquitin ligase activity in a highly conserved N-terminal region.…”

“…20,21 In addition, combination of a Cbl-b inhibitor with an ICI could have potential in overcoming resistance mechanisms, which would improve the standard of care for certain types of cancers. 20 Cbl-b, like other members of the Cbl family, contains all of the structural features required for E3 ubiquitin ligase activity in a highly conserved N-terminal region. 22,23 This region is composed of a substrate binding (TKB, tyrosine kinasebinding) domain and a RING domain, connected by a linker helix region (LHR) (Figure 1).…”