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.

Chimeric antigen receptor T cell (CAR-T) immunotherapy has revolutionized the treatment of relapsed and refractory B cell-derived hematologic malignancies. Currently, there are 6 Food and Drug Administration-approved commercial CAR-T products that target antigens exclusively expressed on malignant B cells or plasma cells. However, concurrent advancement for patients with rarer and more aggressive T cell-derived hematologic malignancies have not yet been achieved. CAR-T immunotherapies are uniquely limited by challenges related to CAR-T product manufacturing and intrinsic tumor biology. In this review tailored for practicing clinician-scientists, we discuss the major barriers of CAR-T implementation against T cell-derived neoplasms and highlight specific scientific advancements poised to circumvent these obstacles. We summarize salient early-stage clinical trials implementing novel CAR-T immunotherapies specifically for patients with relapsed and/or refractory T cell neoplasms. Finally, we highlight novel manufacturing and treatment strategies that are poised to have a meaningful future clinical impact.

With immuno-oncology becoming the standard of care for a variety of cancers, identifying biomarkers that reliably classify patient response, resistance, or toxicity becomes the next critical barrier toward improving care. Multiparametric, multi-omics, and computational platforms generating an unprecedented depth of data are poised to usher in the discovery of increasingly robust biomarkers for enhanced patient selection and personalized treatment approaches. Deciding which developing technologies to implement in clinical settings ultimately, applied either alone or in combination, relies on weighing pros and cons, from minimizing patient sampling to maximizing data outputs, and assessing the reproducibility and representativeness of findings, while lessening data fragmentation toward harmonization. These factors are all assessed while taking into consideration the shortest turnaround time. The Society for Immunotherapy of Cancer Biomarkers Committee convened to identify important advances in biomarker technologies and to address advances in biomarker discovery using multiplexed IHC and immunofluorescence, their coupling to single-cell transcriptomics, along with mass spectrometry–based quantitative and spatially resolved proteomics imaging technologies. We summarize key metrics obtained, ease of interpretation, limitations and dependencies, technical improvements, and outward comparisons of these technologies. By highlighting the most interesting recent data contributed by these technologies and by providing ways to improve their outputs, we hope to guide correlative research directions and assist in their evolution toward becoming clinically useful in immuno-oncology.

Hemangiosarcoma and angiosarcoma are soft-tissue sarcomas of blood vessel–forming cells in dogs and humans, respectively. These vasoformative sarcomas are aggressive and highly metastatic, with disorganized, irregular blood-filled vascular spaces. Our objective was to define molecular programs which support the niche that enables progression of canine hemangiosarcoma and human angiosarcoma. Dog-in-mouse hemangiosarcoma xenografts recapitulated the vasoformative and highly angiogenic morphology and molecular characteristics of primary tumors. Blood vessels in the tumors were complex and disorganized, and they were lined by both donor and host cells. In a series of xenografts, we observed that the transplanted hemangiosarcoma cells created exuberant myeloid hyperplasia and gave rise to lymphoproliferative tumors of mouse origin. Our functional analyses indicate that hemangiosarcoma cells generate a microenvironment that supports expansion and differentiation of hematopoietic progenitor populations. Furthermore, gene expression profiling data revealed hemangiosarcoma cells expressed a repertoire of hematopoietic cytokines capable of regulating the surrounding stromal cells. We conclude that canine hemangiosarcomas, and possibly human angiosarcomas, maintain molecular properties that provide hematopoietic support and facilitate stromal reactions, suggesting their potential involvement in promoting the growth of hematopoietic tumors. Significance: We demonstrate that hemangiosarcomas regulate molecular programs supporting hematopoietic expansion and differentiation, providing insights into their potential roles in creating a permissive stromal-immune environment for tumor progression.

Peripheral T-cell lymphomas (PTCLs) are a rare and heterogenous subset of non-Hodgkin lymphoma characterized by an aggressive clinical course. Historically, the treatment of PTCLs have been analogous to that of aggressive B-cell lymphomas; however, it has been well-established that overall responses and complete remission rates are far inferior using near-identical chemotherapy strategies. Recently, there has been a plethora of newer agents designed to target distinguishing cellular and molecular features of specific PTCL subtypes. These agents have been proven to yield superior anti-lymphoma responses and, in some cases, overall survival in the relapsed, refractory, and frontline treatment setting. In this review, we will summarize and highlight the most influential clinical trials leading to the Food and Drug Administration (FDA) approval of several novel therapeutic agents against PTCL, with an emphasis on emerging studies and strategies to expand their potential use in the frontline treatment setting.

Immuno-oncology is increasingly becoming the standard of care for cancers, with the identification of biomarkers that reliably classify immune checkpoint inhibitor response, resistance, and toxicity becoming the next frontier toward improvements in immunomodulatory treatment regimens. Recent advances in multiparametric, multiomics, and computational data platforms generating an unprecedented depth of data may assist in the discovery of increasingly robust biomarkers for enhanced patient selection and more personalized or longitudinal treatment approaches. Which emerging technologies to implement in future research and clinical settings, used alone or in combination, relies on weighing the pros and cons that aid in maximizing data outputs while minimizing patient sampling, with high reproducibility and representativeness, and minimal turnaround time and data fragmentation toward later private and public dataset harmonization strategies. The Society for Immunotherapy of Cancer Biomarkers Committee convened to identify important advances in biomarker technologies and highlight advances in biomarker discovery using liquid biopsy and in vivo imaging technologies. We address advances in liquid biopsy technologies monitoring cells, proteins, nucleic acids, antibodies, and drugs or analytes and radiomics technologies monitoring whole host-level imaging methods, including immuno-PET and MRI technologies, which are able to couple biomarkers with physical location. We include a summary of key metrics obtained by these technologies and their ease of interpretation, limitations and dependencies, technical improvements, and outward comparisons. By highlighting some of the most interesting recent examples contributed by these technologies and providing examples of improved outputs, we hope to guide correlative research directions and assist in their becoming clinically useful in immuno-oncology.