Understanding and treating the inflammatory adverse events of cancer immunotherapy

Abstract

During the past decade, immunotherapies have made a major impact on the treatment of diverse types of cancer. Inflammatory toxicities are not only a major concern for Food and Drug Administration (FDA)-approved checkpoint blockade and chimeric antigen receptor (CAR) T cell therapies, but also limit the development and use of combination therapies. Fundamentally, these adverse events highlight the intricate balance of pro- and anti-inflammatory pathways that regulate protective immune responses. Here, we discuss the cellular and molecular mechanisms of inflammatory adverse events, current approaches to treatment, as well as opportunities for the design of immunotherapies that limit such inflammatory toxicities while preserving anti-tumor efficacy.

Figure 1.. Organs frequently affected by inflammatory toxicities of checkpoint blockade.

(A) Organs representing the most clinically important sites of inflammatory toxicities induced by PD-1/PD-L1 (left) or CTLA-4/combination (right) blockade. (B) Relationship between incidence and severity for organs affected by checkpoint inhibitor toxicities. (C) Potential factors contributing to susceptibility of checkpoint inhibitor toxicities.

Figure 2.. Modulation of T cell function by antibodies targeting the inhibitory CTLA-4 and PD-1 receptors.

(A) Biology of CTLA-4 receptor. The CTLA-4 inhibitory and CD28 costimulatory receptors bind to the same ligands (CD80/CD86) on antigen presenting cells in lymph nodes. CTLA-4 binds these ligands with higher affinity, thereby reducing ligand availability for CD28. CTLA-4 is stored in an intracellular compartment and transported to the cell surface following initial T cell activation, thereby serving as a negative feedback mechanism. Antibody-mediated inhibition of CTLA-4 function enhances T cell priming by making more CD80/CD86 ligands available for the CD28 costimulatory receptor. Also, the antibody prevents removal of CD80/86 from antigen presenting cells by Tregs. (B) Biology of the PD-1 receptor. PD-1 expression is induced by T cell activation, thereby providing an inhibitory signal that constrains T cell function. IFNγ secreted by activated T cells induces expression of PD-L1 on target cells (such as pancreatic β cells). This pathway inhibits autoimmunity and immunopathology. Antibody-mediated blockade of this pathway enhances T cell activation, resulting in greater cytotoxicity and release of pro-inflammatory cytokines.

Figure 3.. Inflammatory pathways contributing to colon inflammation following checkpoint blockade.

Tissue-resident memory T cells that may be specific for microbial antigens become re-activated following blockade of CTLA-4 and/or PD-1 inhibitory receptors. Re-activated Trm show elevated cytotoxicity, proliferation and inflammatory cytokine (IFNγ) programs. Myeloid cells respond to IFNγ and other cytokines by amplifying the inflammatory response and recruiting T cells from the circulation, thereby overwhelming Treg-mediated suppression. Damage to colon tissue and loss of barrier integrity may result from T cell-mediated cytotoxicity and inflammatory cytokine signaling.

Figure 4.. Proposed functional subgrouping of inflammatory toxicities.

(A) Barrier organs colonized by microbiota harbor an abundant tissue-resident T cell (Trm) population that may recognize microbial antigens. (B) Re-activation of Trm within barrier organs by checkpoint blockade represents an important step in the development of inflammatory toxicities. (C) Internal sterile organs tend to have smaller numbers of infiltrating T cells. (D) Enhanced de novo priming of T cells specific for self-antigens and activation of latent autoreactive T cell clones may represent initial steps in the development of checkpoint blockade induced toxicities in sterile organs, such as endocrine organs or the heart.

Figure 5.. Potential therapeutic targets for inflammatory toxicities induced by checkpoint blockade.

Potential therapeutic agents for checkpoint inhibitor (CPI) toxicities are shown along with their potential impact on tumor immunity. Black outlines represent therapeutic agents with preliminary evidence of clinical activity that may not impair anti-tumor immunity. Grey outlines highlight promising therapeutic targets based on available knowledge on inflammatory toxicities and mechanisms of tumor immunity.

Figure 6.. Inflammatory toxicities induced by CAR T cell therapies.

(A) CAR T cells transduced with a CD19-specific receptor eradicate CD19-expressing leukemia cells while inducing potent myeloid cell activation and release of inflammatory mediators, resulting in cytokine release syndrome (CRS). Indicated CRS therapies are colored according to current clinical use (black) or promising pre-clinical data (grey). (B) CD19-specific T cells can recognize CD19 expressed by perivascular cells at the blood brain barrier. Direct cytotoxicity and indirect cytokine-mediated damage disrupt the blood-brain barrier, resulting in neurological toxicities. Therapies for neurotoxicity are shown colored according to current clinical use (black) or promising pre-clinical data (grey).