Therapeutic intersections: Expanding benefits of CD19 CAR T cells from cancer to autoimmunity.

Anti-CD19 CAR T cells were among the last decade's scientific breakthroughs, achieving remarkable remissions in patients with B cell leukemias and lymphomas. Now, the engineered cell therapies are traversing disease indications into autoimmunity and resolving disease symptoms in patients with systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis.1.

Future perspectives on engineered T cells for cancer.

Chimeric antigen receptor (CAR) T cell therapy has emerged as a revolutionary treatment for hematological malignancies, but its adaptation to solid tumors is impeded by multiple challenges, particularly T cell dysfunction and exhaustion. The heterogeneity and inhospitableness of the solid tumor microenvironment (TME) contribute to diminished CAR T cell efficacy exhibited by reduced cytotoxicity, proliferation, cytokine secretion, and the upregulation of inhibitory receptors, similar to the phenotype of tumor-infiltrating lymphocytes (TILs). In this review, we highlight recent advances in T cell therapy for solid tumors, particularly brain cancer. Innovative strategies, including locoregional delivery and 'armoring' CAR T cells with cytokines such as interleukin (IL)-18, are under investigation to improve efficacy and safety. We also highlight emerging issues with toxicity management of CAR T cell adverse events. This review discusses the obstacles associated with CAR T cell therapy in the context of solid tumors and outlines current and future strategies to overcome these challenges.

Challenges and opportunities in cancer immunotherapy: a Society for Immunotherapy of Cancer (SITC) strategic vision.

Cancer immunotherapy has flourished over the last 10-15 years, transforming the practice of oncology and providing long-term clinical benefit to some patients. During this time, three distinct classes of immune checkpoint inhibitors, chimeric antigen receptor-T cell therapies specific for two targets, and two distinct classes of bispecific T cell engagers, a vaccine, and an oncolytic virus have joined cytokines as a standard of cancer care. At the same time, scientific progress has delivered vast amounts of new knowledge. For example, advances in technologies such as single-cell sequencing and spatial transcriptomics have provided deep insights into the immunobiology of the tumor microenvironment. With this rapid clinical and scientific progress, the field of cancer immunotherapy is currently at a critical inflection point, with potential for exponential growth over the next decade. Recognizing this, the Society for Immunotherapy of Cancer convened a diverse group of experts in cancer immunotherapy representing academia, the pharmaceutical and biotechnology industries, patient advocacy, and the regulatory community to identify current opportunities and challenges with the goal of prioritizing areas with the highest potential for clinical impact. The consensus group identified seven high-priority areas of current opportunity for the field: mechanisms of antitumor activity and toxicity; mechanisms of drug resistance; biomarkers and biospecimens; unique aspects of novel therapeutics; host and environmental interactions; premalignant immunity, immune interception, and immunoprevention; and clinical trial design, endpoints, and conduct. Additionally, potential roadblocks to progress were discussed, and several topics were identified as cross-cutting tools for optimization, each with potential to impact multiple scientific priority areas. These cross-cutting tools include preclinical models, data curation and sharing, biopsies and biospecimens, diversification of funding sources, definitions and standards, and patient engagement. Finally, three key guiding principles were identified that will both optimize and maximize progress in the field. These include engaging the patient community; cultivating diversity, equity, inclusion, and accessibility; and leveraging the power of artificial intelligence to accelerate progress. Here, we present the outcomes of these discussions as a strategic vision to galvanize the field for the next decade of exponential progress in cancer immunotherapy.

CD5 deletion enhances the antitumor activity of adoptive T cell therapies.

Most patients treated with US Food and Drug Administration (FDA)-approved chimeric antigen receptor (CAR) T cells eventually experience disease progression. Furthermore, CAR T cells have not been curative against solid cancers and several hematological malignancies such as T cell lymphomas, which have very poor prognoses. One of the main barriers to the clinical success of adoptive T cell immunotherapies is CAR T cell dysfunction and lack of expansion and/or persistence after infusion. In this study, we found that CD5 inhibits CAR T cell activation and that knockout (KO) of CD5 using CRISPR-Cas9 enhances the antitumor effect of CAR T cells in multiple hematological and solid cancer models. Mechanistically, CD5 KO drives increased T cell effector function with enhanced cytotoxicity, in vivo expansion, and persistence, without apparent toxicity in preclinical models. These findings indicate that CD5 is a critical inhibitor of T cell function and a potential clinical target for enhancing T cell therapies.