Background The presence of regulatory T cells (Tregs) in solid tumors attenuates the ability of immune cells to mediate an effective response to cancer. Expansion and activation of intratumoral Tregs is a proposed mechanism of PD-1/PD-L1 checkpoint inhibition resistance and elimination of these cells could facilitate an immune response to tumors. Single cell transcriptomic and flow cytometric analysis of tumor-associated immune cells revealed enhanced expression of CD30 on an activated subset of Tregs, suggesting that treatment with an anti-CD30 molecule could selectively deplete this subset of intratumoral Tregs. Moreover, anti-PD1 treatment of intratumoral T cells selectively enhanced expression of CD30 on Tregs compared with either CD4+ or CD8+ T cells, suggesting compatibility with immune checkpoint inhibitor therapy. The anti-CD30 antibody-drug conjugate (ADC) brentuximab vedotin is approved for the treatment of advanced classical Hodgkin lymphoma and other CD30-expressing lymphomas. It is currently being tested in combination with pembrolizumab for the ability to deplete Tregs and increase immune checkpoint activity in anti-PD-1-refractory metastatic melanoma and NSCLC (NCT04609566).
Methods Preliminary analysis of IHC and RNA-seq data from paired biopsies in responder patients suggests increased tumor-infiltrating CD8+ T cells post treatment. SGN-35T, an anti-CD30 ADC with the same antibody (cAC10) and cytotoxic payload (monomethyl auristatin E) as brentuximab vedotin, contains a novel tripeptide linker comprised of D-leucine-alanine-glutamate (DLAE) and was developed to improve the tolerability profile while leveraging the known activity of brentuximab vedotin.
Results In addition to cytotoxic activity on CD30-expressing tumor cells, SGN-35T depleted CD30-expressing Tregs in vitro, while in contrast CD8+ T cells were not affected. This may be due to the variable expression of drug efflux transporters which differs across T cell subsets and activation states, with Tregs demonstrating limited efflux capacity in contrast to naive CD8+ T cells and memory CD8+ T cells.
Conclusions Thus, the cytotoxic activity of SGN-35T on CD30-expressing Tregs is likely a combination of the enrichment of CD30 expression on activated Tregs coupled with reduced drug efflux capacity. Together, these data support future clinical investigation of SGN-35T in combination with anti-PD-1/PD-L1 checkpoint inhibitors in solid tumors.
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