Establishing a model system for evaluating CAR T cell therapy using dogs with spontaneous diffuse large B cell lymphoma

Multiple rodent and primate preclinical studies have advanced CAR T cells into the clinic. However, no single model accurately reflects the challenges of effective CAR T therapy in human cancer patients. To evaluate the effectiveness of next-generation CAR T cells that aim to overcome barriers to durable tumor elimination, we developed a system to evaluate CAR T cells in pet dogs with spontaneous cancer. Here we report on this system and the results of a pilot trial using CAR T cells to treat canine diffuse large B cell lymphoma (DLBCL). We designed and manufactured CD20-targeting, second-generation canine CAR T cells for functional evaluation in vitro and in vivo using lentivectors to parallel human CAR T cell manufacturing. A first-in-species trial of five dogs with DLBCL treated with CAR T was undertaken. Canine CAR T cells functioned in an antigen-specific manner and killed CD20+ targets. Circulating CAR T cells were detectable post-infusion, however, induction of canine anti-mouse antibodies (CAMA) was associated with CAR T cell loss. Specific selection pressure on CD20+ tumors was observed following CAR T cell therapy, culminating in antigen escape and emergence of CD20-disease. Patient survival times correlated with ex vivo product expansion. Altering product manufacturing improved transduction efficiency and skewed toward a memory-like phenotype of canine CAR T cells. Manufacturing of functional canine CAR T cells using a lentivector is feasible. Comparable challenges to effective CAR T cell therapy exist, indicating their relevance in informing future human clinical trial design

Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia

Tolerance to self-antigens prevents the elimination of cancer by the immune system 1,2 . We used synthetic chimeric antigen receptors (CARs) to overcome immunological tolerance and mediate tumor rejection in patients with chronic lymphocytic leukemia (CLL). Remission was induced in a subset of subjects, but most did not respond. Comprehensive assessment of patient-derived CAR T cells to identify mechanisms of therapeutic success and failure has not been explored. We performed genomic, phenotypic and functional evaluations to identify determinants of response. Transcriptomic profiling revealed that CAR T cells from complete-responding patients with CLL were enriched in memory-related genes, including IL-6/STAT3 signatures, whereas T cells from nonresponders upregulated programs involved in effector differentiation, glycolysis, exhaustion and apoptosis. Sustained remission was associated with an elevated frequency of CD27+CD45RO-CD8+ T cells before CAR T cell generation, and these lymphocytes possessed memory-like characteristics. Highly functional CAR T cells from patients produced STAT3-related cytokines, and serum IL-6 correlated with CAR T cell expansion. IL-6/STAT3 blockade diminished CAR T cell proliferation. Furthermore, a mechanistically relevant population of CD27+PD-1-CD8+ CAR T cells expressing high levels of the IL-6 receptor predicts therapeutic response and is responsible for tumor control. These findings uncover new features of CAR T cell biology and underscore the potential of using pretreatment biomarkers of response to advance immunotherapies

CAR T cells targeting BCMA and CD19 for newly diagnosed and relapsed multiple myeloma patients responding to current therapy

We conducted a phase 1 clinical trial of anti-BCMA CAR T cells (CART-BCMA) with or without anti-CD19 CAR T cells (huCART19) in multiple myeloma (MM) patients responding to third-orlater- (Phase A, N=10) or high-risk patients responding to first-line therapy (Phase B, N=20), followed by early lenalidomide or pomalidomide maintenance. We observed no high-grade CRS and only one instance of low-grade neurologic toxicity. In vivo CART-BCMA expansion was comparable to that previously observed with CART-BCMA in relapsed/refractory MM. Early maintenance therapy was safe and feasible and coincided with CAR T cell re-expansion and late-onset clinical response in some patients. Pre-treatment MM cell-surface BCMA levels were unexpectedly low despite no prior exposure to anti-BCMA therapy. Despite low disease burden and evidence of anti-MM activity in most patients, only 4 subjects converted to complete response. Outcomes with CART-BCMA + huCART19 were similar to CART-BCMA alone

Outcomes in Newly Diagnosed Atrial Fibrillation and History of Acute Coronary Syndromes: Insights from GARFIELD-AF

BACKGROUND: Many patients with atrial fibrillation have concomitant coronary artery disease with or without acute coronary syndromes and are in need of additional antithrombotic therapy. There are few data on the long-term clinical outcome of atrial fibrillation patients with a history of acute coronary syndrome. This is a 2-year study of atrial fibrillation patients with or without a history of acute coronary syndromes