A3.4 Immune-mediated toxicity

Topic

The immune system, once restored by immunotherapy, does not perfectly distinguish between the tumor and the rest of the patient's body: when immunological tolerance—the mechanism that normally prevents the immune system from attacking the patient's own tissues—breaks down, that same restored immune system can attack normal host tissues; this immune-mediated toxicity is the hallmark toxicity of immunotherapy.

The underlying mechanism of this immune-mediated toxicity is straightforward: the very process that amplifies the restored immune system's cytotoxic capacity against the tumor—by reactivating autoreactive T cells and increasing the patient's overall inflammatory tone—can also activate T cells that recognize autoantigens present in normal host tissues; it is these T cells, activated against autoantigens, that ultimately attack those normal tissues.

At its core, this immune-mediated toxicity reflects a fundamental trade-off inherent to immunotherapy: since there is currently no way to amplify the restored immune system's cytotoxic capacity solely against the tumor, boosting that anti-tumor cytotoxicity inevitably increases the immune system's potential to attack other tissues in the patient's body.

The severity of this immune-mediated toxicity in any given patient depends on a combination of factors: the degree of resemblance between tumor neoantigens—the tumor-specific antigens targeted by immunotherapy—and the autoantigens found in normal host tissues; the administered dose and the specific molecular "brake" that was blocked; and, finally, the patient's genetic susceptibility—that is, the set of genes determining how an individual recognizes their own tissues, as well as the genetic variants present in genes that regulate the immune system. Overall, immune-mediated toxicity demonstrates that the very same restored immune system that gives immunotherapy its ability to destroy the tumor is, at the same time, the source of its primary risk: it is not a side effect unrelated to the therapeutic mechanism, but rather the other side of the very mechanism that restores the immune system's cytotoxic capacity against the tumor.

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