CD30-Directed CAR-T Cells Co-Expressing CCR4 in Relapsed/Refractory Hodgkin Lymphoma and CD30+ Cutaneous T Cell Lymphoma

Chimeric antigen receptor T cells targeting CD30 (CD30.CAR-T) have shown high response rates, including some durable remissions, in patients with relapsed/refractory (r/r) classical Hodgkin lymphoma (HL) (Ramos et al., JCO 2020). However, some patients are non-responders or eventually relapse after therapy. Because CD30 expression is retained in relapsing tumors, recurrence may be due to the insufficient persistence of CAR-Ts within the highly immunosuppressive tumor microenvironment of HL. We therefore reasoned that with enhanced trafficking to the tumor site, CD30.CAR-Ts would have increased opportunities to eliminate tumors before inhibitory mechanisms become predominant. This is especially relevant for HL, where Hodgkin Reed Sternberg (HRS) cells produce CCL17 (thymus and activation-regulated chemokine) to create a physical and inhibitory barrier to cytotoxic T cells. We have previously shown that CD30.CAR-Ts co-expressing the cognate receptor for CCL17, CCR4 (CCR4.CD30.CAR-Ts), have improved tumor homing and anti-lymphoma activity compared with CD30.CAR-Ts that do not express CCR4 (Di Stasi et al., Blood 2009). CCR4.CD30.CAR-Ts should also be more effective in CD30+ cutaneous T-cell lymphomas (CTCL) due to enhanced trafficking to the skin. We present the preliminary results of a clinical trial assessing the safety (primary objective) of this novel strategy and its efficacy compared to CD30.CAR-Ts lacking CCR4 in patients with r/r HL and CD30+ CTCL (NCT03602157).