Novel Immunotherapeutic Approaches for Hodgkin Lymphoma

The outcome of patients with relapsed/refractory Hodgkin Lymphoma (HL) for whom salvage therapy or stem cell transplant have failed is poor. HL tumor cells (HRS) cells universally express CD30, which is an excellent target for directed therapy such as the antibody drug conjugate brentuximab vedotin (BV). Patients with relapsed HL can also respond to checkpoint inhibitors, emphasizing the susceptibility of this tumor to T-cell-mediated immune control. The adoptive transfer of chimeric antigen receptor T (CAR-T) cells, which combine antibody-mediated antigen specificity with the effector function and replication potential of T lymphocytes, offers the opportunity to infuse large numbers of T cells with defined antigen-specificity and MHC-independent tumor targeting. In two parallel and simultaneously conducted phase 1/2 dose-escalation studies, we administered CD30-specific CAR-T (CD30.CAR-T) cells after lymphodepletion to patients with HL that had relapsed after multiple lines of therapy, including BV, checkpoint inhibitors and stem cell transplant. We observed an excellent safety profile, with modest and self-limited cytokine release syndrome and no neurologic toxicity. The overall response rate was 78%, including 18 patients (67%) with complete responses, and the 1 year progression free survival was 47% (95% CI: 25% - 67%). Despite these promising results, unsolved obstacles include CAR-T cell trafficking and persistence in the tumor site. HL is characterized by a unique tumor microenvironment that creates a physical barrier and a hostile niche for CD30.CAR-T cells. Expression of PD-1 on CD30.CAR-T cells indicates that these cells likely remain susceptible to inhibition by PD-L1 in the tumor, and suggests that the combination of CD30.CAR-T cells with checkpoint blockade should be investigated. Enhancing CAR-T cell trafficking to tumor sites should also tip the delicate balance between effector and inhibitory mechanisms towards the former. Since the tumor microenvironment of HL is rich in TARC (thymus and activation regulated chemokine/CC chemokine ligand 17), we have initiated a clinical study in which CD30.CAR-T cells are further modified to co-express the cognate receptor (CCR4) for TARC to improve their tumor homing (NCT03062157).