CAR-T Therapy: Safety, Efficacy, and Immune-Escape Mechanisms

This is a retrospective and prospective, non-interventional, biological observational study involving adult patients who receive or have received Chimeric Antigen Receptor T-cell (CAR-T) therapy or bispecific antibody therapy at IRCCS Ospedale San Raffaele.

The primary objective is to characterize patients undergoing these treatments to identify biomarkers predictive of treatment response and toxicity, support therapeutic decision-making, and identify novel therapeutic targets. The study will investigate tumor cell and tumor microenvironment signatures, biomarkers of CAR-T product fitness, and clinical variables potentially associated with treatment outcomes. These variables will include prior lines of treatment, T-cell composition before manipulation, the composition and activation status of host T-cell and myeloid cell populations, timing of cell collection, and bridging therapy.

The study will also monitor the kinetics and phenotypic and functional characteristics of CAR-T cells following infusion to investigate their association with treatment efficacy and safety. Furthermore, the study aims to improve understanding of the biological mechanisms underlying treatment resistance and immune escape, with the ultimate goal of optimizing existing therapeutic platforms.

The primary endpoints are overall response rate (ORR), defined as the proportion of patients achieving complete response (CR) or partial response (PR) following treatment ; the incidence of cytokine release syndrome (CRS); the incidence of neurotoxicity; and progression-free survival (PFS), defined as the time from the applicable treatment initiation or infusion to disease progression or death, according to the study-specific assessment criteria.

These endpoints will be evaluated in relation to biological signatures, CAR-T product characteristics, clinical variables, and post-infusion CAR-T cell kinetics and functionality.

Secondary objectives include the establishment, implementation, and maintenance of an integrated database combining clinical information with data obtained through laboratory monitoring. The study will also assess the applicability of biomarkers previously identified as predictive of response and/or toxicity in CAR-T-treated patients to patients receiving bispecific antibody therapy.

Biological samples will be collected as part of routine clinical practice or retrieved from existing biological sample collections, where available. No experimental diagnostic procedures, investigational medicinal products, or investigational medical devices will be introduced as part of the study.

Eligibility criteria

• Eligible participants must be adults aged 18 years or older and meet at least one of the following criteria:
• Candidates for CAR-T-cell therapy who have signed at least an initial informed consent for evaluation for this treatment at the study center.
• Patients who have previously provided informed consent for participation in the Hematological Malignancies Biobank (Biobanca Neoplasie Ematologiche) and for whom stored biological samples are available.
• Candidates for bispecific antibody therapy who have signed at least an initial informed consent for evaluation for this treatment at the study center.

Exclusion Criteria

• Patients participating in clinical protocols that explicitly prohibit participation in biological observational studies will be excluded.