Offtumor

Off-tumor, also written offtumor, is a term used in oncology to describe adverse effects that arise when therapies aimed at tumor-associated targets also affect normal tissues that express the same target or antigen. The concept is used to describe risks in targeted therapies and immunotherapies and is a key consideration in drug development and clinical use.

Off-tumor effects can be categorized as on-target off-tumor, where the therapeutic target is present on both tumor and normal cells, and as off-target toxicities, where the drug engages a different antigen with unintended tissue distribution. Mechanisms include shared antigen expression on normal tissues, cross-reactivity due to structural similarity, antigen shedding, or unexpected biodistribution that concentrates the agent in non-tumor sites.

In practice, off-tumor effects are commonly discussed for monoclonal antibodies and CAR-T cell therapies. For example, therapies directed at CD19 deplete normal B cells, causing B-cell aplasia. EGFR inhibitors can provoke skin and gastrointestinal toxicities because EGFR is expressed in normal epithelia. Antibody-drug conjugates may cause toxicity if the cytotoxic payload affects normal cells that express the target.

Mitigation strategies include careful antigen selection to maximize tumor specificity, affinity tuning to discriminate low-density normal expression, regional or controlled delivery, safety switches in cellular therapies, and vigilant monitoring with prompt management of adverse events.

The concept remains an active area of research in oncology, guiding target discovery, preclinical testing, and the design of safer therapies. It is related to broader topics of precision medicine and adverse event management.