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EBMT 2018 | CD30-specific CAR-T: Phase I dose escalation study

A special session on CAR-T future perspectives and beyond took place on 21 March 2018 at the 44th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT). A talk was presented by Carlos Ramos, Associate Professor at the center for cell and gene therapy, Baylor College of Medicine, Houston, Texas, on CD30-specific CAR-redirected lymphocytes.

Dr. Ramos began his talk by stating that CD30 presented as a promising target, especially for Hodgkin lymphoma (HL), and has previously been successfully targeted with antibodies conjugated with cytotoxic agents. He added that there has been a consistency in the data with regards to activity for CD30-specific CARs in animal models in HL.

Dr. Ramos and colleagues conducted a phase I dose escalation clinical study (NCT01316146) that assessed CD30-specific CAR-Ts in patients with CD30 positive malignancies with active disease and who were not successful with standard treatment. Nine patients were included in the study (median age = 33 years, range 20–71) who had either HL (n = 7) or anaplastic large cell lymphoma (ALCL) (n = 2). Three dose levels (DL) were investigated; two patients received 2 x 107 CAR+ cells/m2 (DL1), two patients received 1 x 108 CAR+ cells/m2 (DL2) and five patients received 2 x 108 CAR+ cells/m2 (DL3). No lymphodepleting chemotherapy was used in this study before infusion.

Some evidence was seen of a response relationship at the different dose levels for example, patients with DL1 had a lower expansion of T-cells in vivo after infusion compared with those in DL3. Dr. Ramos explained that after infusion, levels of cytokines associated with cytokine release syndrome (CRS) were much lower than what is seen in other CAR-T trials. Dr. Ramos stated that there was no evidence of CRS observed in the nine patients. Additionally, the viral immunity of the patients was not compromised by CD30 CAR-Ts. The results showed that three patients had progressive disease, two had a complete response and three had stable disease. However, Dr. Ramos said he, “hoped to have seen better results in this setting”.

In order to optimize this therapy, Dr. Ramos recommended good host lymphodepletion for CAR T-cell expansion and that this may be hindered by immune checkpoints. He suggested that lymphodepleting chemotherapy could improve CAR-T expansion as demonstrated by another phase I dose escalation trial RELY-30 (NCT02917083). Lymphodepleting chemotherapy DL1 achieved expansion levels close to DL3 without lymphodepleting therapy and better responses were seen than in the first protocol.

Dr. Ramos concluded that CD30 was an example that CARs can be developed beyond CD19 and that it is relatively safe. Expansion is dose-dependent and lymphodepleting chemotherapy can improve responses. He cautioned that expansion increase may increase toxicity and therefore it may be associated with CRS. The next step would be to determine where this treatment fits into standard therapy. Dr. Ramos provided an overview of his talk in an interview with the Lymphoma Hub.

References
  1. Ramos C. CD30-specific chimeric antigen receptor-redirected lymphocytes. Oral Presentation SS4-1. EBMT 44th Annual Meeting, Lisbon, Portugal
  2. Ramos C. et al. Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes. The Journal of Clinical Investigation. 2017 Sep 1; 127(9): 3462–3471. doi: 10.1172/JCI94306. Epub 2017 Aug 14
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