Research summary IIS/FJD

The Immunotherapy subgroup belonging to the Experimental Haematology group of the Instituto de Investigación Sanitaria/Fundación Jimenez Díaz, is a new group created from the incorporation of Beatriz Martín Antonio as a Miguel Servet researcher at the Fundación Jiménez Díaz. Dr. Matín Antonio thus continues her line of research initiated at her former institution (Hospital Clinic, Barcelona) where she was responsible for the creation of an academic CAR for patients with multiple myeloma that is currently being administered to patients with optimal results (NCT04309981). Dr. Martín has an H=18 index, with 43 scientific articles, being lead author in 20 of them. 33 articles in Q1. He has supervised 9 Master students, one PhD thesis and two in progress.

Currently, the main limitations of CAR therapy in adults with mature B-cell haematological malignancies (multiple myeloma and non-Hodgkin’s lymphoma) are the loss of the target antigen, and the lack of persistence of CARs, the latter being an important barrier in solid tumours. Therefore, the main lines of research of the group are:

  1. Search for new targets that do not induce loss of the target antigen: In particular, the group has begun the creation of different CARs against CD79b, a valid target for NHL. In addition, the creation of bicistronic CARs directed at two targets or a cocktail of CAR cells are options that avoid this phenomenon. In this sense, the group has CARs against CD19, BCMA and CD79b where they will test in both NHL and MM the creation of bicistronic CARs and CAR cocktails to determine the best option for the clinic.
  2. Increase CAR persistence: the group has shown in the past that the combined use of CAR-T cells with cord blood-derived NK cells (CB-NK) improves the efficacy and persistence of treatment in MM and decreases parameters associated with CAR cell senescence. We now aim to apply this strategy to NHL and oral squamous cell carcinomas (OSCC). In the case of OSCC, the group collaborates with CIEMAT, which is working on this type of tumour.
  3. The elimination of mechanisms associated with immune cell senescence or “immunosenescence”: A critical factor for CAR-T cell persistence is that T cells are not terminally differentiated (immunosenescent), as this decreases their longevity and proliferative capacity, thereby decreasing their persistence in vivo. In elderly patients and with chemotherapy treatments, naïve, central memory stem (MCS) and central memory (CM) T cells are observed to decrease as they differentiate into effector memory (EM) and effector cells. In addition, the production of CARs leads to an expansion that also induces their differentiation. The group is looking for drugs that can be used during CAR production to prevent this differentiation.
  4. In elderly patients, immunosenescent cells have a limited function, including a defective elimination of senescent tumour cells that remain residual after treatments. These senescent tumour cells can transfer senescence to CAR cells by further increasing their immunosenescence. The group is studying these mechanisms to find the secreted factors responsible and create new 4th generation CARs that inhibit them.