“Clone-specific” antibody-drug conjugates: an innovative strategy in the treatment of T-cell cancers

In a recent study published in Nature, Nichakawade et al. provided proof-of-principle data on innovative strategies to target and eliminate cancerous T-cells while sparing healthy T-lymphocytes, addressing the urgent clinical need posed by the mostly aggressive and treatment-refractory T-cell lymphomas. 1This research represents a significant milestone in overcoming major obstacles in immunotherapies for these cancers.Choosing the right target: Approaches like antibody-drug conjugates (ADC) or CAR-T-cells have revolutionized the treatment of B-cell lymphomas.However, T-cell malignancies have drastically less benefited from these advancements.Reasons for this are their rarity and marked heterogeneity.Hence, identifications of highly discriminatory and targetable antigens have been challenging in these hematologic neoplasms.A notable exception is the ADC Brentuximab-vedotin (BV) that is directed against the surface protein CD30, which is particularly abundant in anaplastic large cell lymphoma (ALCL) and only rarely expressed on normal T-cells.The success of BV illustrates the potential of precise targeting of quasi-selective T-cell lymphoma antigens.By delivering its microtubule disrupting payload MMAE directly to CD30 + cancer cells, BV, meanwhile, an established standard in first-line or second-line settings in ALCL, has significantly improved treatment efficacy and patient survival while minimizing toxicity, both in combination with chemotherapy or as a single agent. 2 Another challenge in devising T-cell targeted therapies without good discrimination between malignant vs normal T-cells is the therapy-related T-cell hypoplasia that results in severe immunosuppression, thought to be of more life-threatening potential than B-cell depletion.Mode of execution: When using T-cells as effector cells (i.e., a CAR-T-cell approach) against T-cell tumors there are additional hurdles to overcome.First, in-vitro and in-patient expansion can be severely impaired by self-directed killing among CAR-T-cells that express that therapeutic antigen themselves -the so-called fratricide.A second shortcoming of using autologous T-cell harvests as the source for therapeutic (CAR) T-cells is product contamination by malignant T-cells with all the implications around their immunologically hypo-functional state or the transduction of another growth-promoter (CAR) potentially propelling clonal outgrowth.Moreover, prior T-cell depleting (chemo)therapies limit the yield of competent CAR-T-cells.Finally, the clinical scenarios of refractory T-cell malignancies often dictate the immediate application of effective salvage strategies followed by the swift application of the more definitive cell-therapeutic approach.Here, off-the-shelf solutions would overcome the limitations by the time-intensive process of CAR-T-cell production.