Immunotherapy has revolutionized cancer treatment over the last decade. Adoptive cell immunotherapy with T-cells genetically redirected to a tumor-specific antigen using CARs has achieved impressive complete response rates in (R/R) “advanced” B-cell malignancies. However, the CAR T-cell field is still in its infancy and major barriers need to be overcome for its full potential to be realized; for instance, i) CAR-associated toxicities including life-threatening cytokine release syndrome remain common, ii) >50% of patients relapse as soon as 6–12 months after CAR T-cell infusion, frequently associated with CAR T-cell exhaustion, iii) predictive markers for CAR T-cell responses are unavailable [Majzner, RG et al. Cancer Discov, 2018; Brentjens, RJ et al. Blood, 2011]. Most importantly, CAR T-cell therapies beyond B-cell malignancies are lagging behind due to expected “on-target off-tumor” toxicities and/or the absence of a bona fide therapeutic and safe antigen [Hombach, A., et al. Expert Rev Clin Immunol, 2017]. T-cell malignancies spanning T-ALL and T-cell lymphomas represent very heterogeneous entities diagnosed at any age during lifetime, and commonly have an unfavorable prognosis. Patients with R/R T-ALL have a dismal outcome, and no further therapeutic options are available [Litzow, M.R. et al. Blood, 2015]. Indeed, there are no immunotherapeutic strategies (including CAR T-cells) approved for T-ALL because of the shared expression of target antigens between CAR T-cells and T-ALL blast cells. For this reason, CAR T-cell therapy against pan-T-cell antigens will induce CAR T-cell self- targeting/fratricide and T-cell aplasia, leading to life-threatening immunodeficiency [Fleischer, LC. J Hematol Oncol, 2019].
We have identified the CD1a antigen as a safe target for CD1a+ cortical T-ALL (coT-ALL), a major subgroup of T-ALL (encompassing 40–45% of patients), and has developed a CD1a-specific CAR. CD1a CAR T-cells are fratricide- resistant, show no off-tumor toxicity, and have robust anti-leukemic activity and long-term persistence in vivo, pointing to its safe therapeutic use for coT-ALL [Sanchez-Martinez, D et al. Blood 2019]. Our CD1a-directed CAR T-cells constitute a unique immunotherapeutic approach for coT-ALL and T-LyL and we have consolidated final technical and biological improvements and GMP-compliant manufacturing of our newly developed CD1a-directed chimeric antigen receptor (CAR) T-cells in compliance with the requirements of the Spanish Regulatory Agency of Medicines and Medical Devices (AEMPS) for advanced adoptive cellular therapies. Resulting from this ERC-PoC project the final Investigational Medicinal Product Dossier (IMPD) of the CAR-CD1a T-cells has been submitted to AEMPS for regulatory approval to launch a pan-European open Phase Ib First-In-Human Clinical Trial with the hCAR-CD1a for relapse/refractory (R/R) cortical T-cell Acute Lymphoblastic Leukemia (coT-ALL) and T-cell lymphoblastic lymphoma (T-LyL) in January 2023, thus ensuring social and health value of this innovative immunotherapy for this patient group.
