Targeted Tumor Vaccines
Dr. Angel Cid-Arregui
Our aim is to develop strategies that might be useful in adoptive cell therapy (ACT) of solid tumors. One such strategy developed recently by our research group is the combination, in the same effector cell, of a TCR and a chimeric antigen receptor (CAR), each targeting a different antigen. This approach could be applied to enhance the efficacy of TCR-based cancer immunotherapy and to overcome limitations in the efficacy of ACT due to intratumoral antigen heterogeneity.
Our Research
We are interested in identifying T cell receptors (TCRs) that recognize specific tumor antigens presented by the major histocompatibility complex class I (HLA) on the surface of tumor cells. Immune cells engineered to have an anti-tumor TCR may be effective in the treatment of eventually any type of cancer. However, because of some degree of promiscuity in antigen recognition, TCR-based immunotherapy may cause adverse effects due to engagement with one or more antigen(s) in healthy tissues, which may have homology with the target tumor antigen. To minimize such on-target off-tumor effect, we have developed a dual-receptor strategy consisting in combining a weak TCR, selected from the T cell repertoire of healthy donors, with a weak chimeric antigen receptor (CAR), understanding “weak” as low-avidity receptors. We have been able to show that NK and T cells armed with such dual receptors are highly cytotoxic against cancer cell lines expressing the antigens recognized by the respective receptors, while NK and T cells armed with only one of the receptors exhibited low cytotoxic activity against the same tumor cells and no activity against cells not expressing the target antigens.
Projects
Dual TCR/CAR NK and T cells
The human papillomavirus type 16 (HPV16) causes a large fraction of genital and oropharyngeal carcinomas. To maintain the transformed state, the tumor cells must continuously synthesize the E6 and E7 viral oncoproteins, which makes them tumor-specific antigens. Indeed, specific T cell responses against E6 and E7 have been well documented and CD8+ T cells engineered to express T cell receptors (TCRs) that recognize epitopes of E6 or E7 have been tested in clinical studies with promising results, yet with limited clinical success. Using CD8+ T cells from peripheral blood of healthy donors, we have identified two novel TCRs reactive to an unexplored E618-26 epitope. These TCRs showed limited standalone cytotoxicity against E618-26-HLA-A*02:01-presenting tumor cells. However, a single-signaling domain chimeric antigen receptor (ssdCAR) targeting L1CAM, a cell adhesion protein frequently overexpressed in HPV16-induced cancer, prompted a synergistic effect that significantly enhanced the cytotoxic capacity of NK-92/CD3/CD8 cells armored with both TCR and ssdCAR when both receptors simultaneously engaged their respective targets, as shown by live microscopy of 2-D and 3-D co-cultures. Thus, virus-specific TCRs from the CD8+ T cell repertoire of healthy donors can be combined with a suitable ssdCAR to enhance the cytotoxic capacity of the effector cells and, indirectly, their specificity.
Team
4 Employees
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Dr. Angel Cid-Arregui
Group head
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Isaac Quiros Fernandez
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Ruken Süleymanoglu
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Aoife Tritta
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