PROJECT ABSTRACT Despite the development of anti-CD30 antibody-based therapies and use of checkpoint inhibitors, CD30+ malignancies remain difficult to eradicate, with relapses occurring in a significant proportion of patients. The engineering of chimeric antigen receptors (CARs) in T cells has propelled the rapid generation of tumor specific cells, increasing the clinical applicability of adoptively-transferred-cell therapies. We have developed immune based therapies based on T cells redirected with a CAR to target the CD30 antigen, and shown in a phase I/II trial that their adoptive transfer in patients with relapsed/refractory (r/r) Hodgkin's Lymphoma (HL) is safe and produces antitumor activity, including complete responses. We now propose to further increase the response rate and long-term durability of complete responses in patients with CD30+ malignancies by overcoming a major barrier of CD30.CAR T cell based approaches. We will conduct a phase I clinical trial in patients with r/r CD30+ malignancies including HL and cutaneous T cells lymphomas (CTCL), with T cells engineered to coexpress the CD30.CAR and the specific chemokine receptor CCR4, to demonstrate that enhanced migration and trafficking to the tumor further improves antitumor activity. We will then monitor (both systemically and locally, in the tumor microenvironment) immune functions and repertoire in patients with CD30+ malignancies receiving CAR T cells, to identify strengths and limits of our approach for proposing rationale combination therapies. Finally, we plan to study the myeloid cells signatures in these patients and how it contributes in shaping the pro- tumorigenic landscape in the context of CAR-T cell therapies. On completion of our study we will know the clinical impact of directed homing of CAR-Ts on in vivo functionality, the effects and contribution on immune functions and on the pro-tumorigenic landscape associated with these therapies. All components to execute the study are in place and we have sufficient individual and institutional experience to ensure the study will be completed and analyzed as planned