Tumor Immunology & Immunotherapy Group

Mounting evidence indicates that neoantigens play a central role in the clinical efficacy of cancer immunotherapies. With support from the BBVA Foundation’s Comprehensive Program of Cancer Immunotherapy & Immunology (CAIMI-I and CAIMI-II), as well as other funding agencies, and through our long-standing collaboration with Elena Garralda, Group Leader of VHIO’s Early Clinical Drug Development Group, and Director of the Research Unit for Molecular Therapy of Cancer (UTIM) – CaixaResearch, we are conducting a phase I clinical trial to evaluate the safety and tolerability of neoantigen-selected tumor-infiltrating lymphocytes (TILs).

This ongoing clinical trial, funded by the Instituto de Salud Carlos III (ISCIII), employs a highly personalized strategy (Figure) to screen for T-cell–mediated recognition of mutated antigens. In this pilot study, we aim to treat up to 10 patients with epithelial cancers and melanoma refractory to standard therapies. By enriching for neoantigen-reactive lymphocytes, we seek to extend the clinical efficacy of TIL therapy beyond melanoma.

In parallel, our group is involved in several additional clinical trials in collaboration with Elena Garralda and other academic centers in Barcelona, evaluating non-selected, ex vivo–expanded TILs for the treatment of melanoma, germ cell tumors, and cancers harboring mutations in the SWI/SNF complex. Among these, the PragmaTIL trial is a multicenter study funded by the EU Horizon program that aims to reduce the toxicity associated with high-dose IL-2 administration. Notably, this trial represents an important regulatory innovation, given the decentralized nature of TIL manufacturing.

One of our group’s strategic goals is to develop approaches that harness the circulating tumor-reactive lymphocyte repertoire. We have shown that tumor-reactive T cells can frequently be detected in the peripheral blood of cancer patients, irrespective of tumor type. The ability to track and monitor tumor-reactive CD8⁺ and CD4⁺ T cells in blood holds substantial therapeutic potential, although this approach remains challenging due to the low frequency of these cells. We have contributed to defining a phenotypic signature that enables the identification and enrichment of tumor- and neoantigen-reactive T cells from peripheral blood.

Importantly, as part of the transition toward minimally invasive strategies, we have also demonstrated the use of circulating tumor DNA (ctDNA) to identify neoantigens, providing a non-invasive method to characterize tumor-specific antigens. In addition, we are developing a computational pipeline for comprehensive single-cell profiling of peripheral blood T-cell responses in patients treated with immune checkpoint inhibitors (ICIs) and cancer vaccines, with the aim of better understanding the determinants of treatment response.

Our group is also committed to developing high-throughput technologies to decipher the landscape of tumor antigens that enhance cancer cell susceptibility to immune attack, and to advance understanding of shared neoantigens and mechanisms of resistance to T-cell–mediated cytotoxicity.

Figure: Personalized approach to identify tumor and neoantigen-specific TILs. A) We sequence normal and tumor DNA to identify all the non-synonymous mutations. B) In parallel we attempt to generate a tumor cell line. When generated, we isolate the peptide-MHCI complexes, and we identify the peptides presented by MHCI by the tumor cell line by Mass spectrometry. C) Finally, we screen the TILs expanded from the tumor for recognition of the candidate neoantigen peptides identified in A) or eluted from MHCI in B).