CD137 mAb

Subsequent administration of CD137 agonists enhanced T cell activation and cytolytic activity within bone marrow, without exacerbating GVHD. Thus, PT-Cy provides a platform for optimizing immunotherapy after alloSCT.

The CAR consists of the single-chain variable fragment of the antibody (scFv) targeted to a tumor-associated antigen which is recognized in an MHC-independent fashion; the scFv is coupled via an extra-cellular hinge domain and transmembrane domain to an intracellular signaling domain, typically the CD3ζ chain of the T cell receptor.7 Autologous T-cells are collected from peripheral blood via venipuncture or apheresis procedure and transduced with the CAR construct via a lentiviral or retroviral vector, or using electroporation and a transposon/transposase system.8 Cells are cultured and expanded ex vivo either using CD3/28 beads or artificial antigen-presenting cells and specific cytokines prior to infusion.9,10 CAR-Ts persistence and clinical activity in vivo can be enhanced by the addition of a co-stimulatory molecule to the CAR construct (second generation CAR), usually CD28 or CD137 (4-1BB).11-13 An initial report in a highly-refractory CLL patient treated with a second generation, anti-CD19 CAR-T utilizing 4-1BB as the co-stimulatory domain generated great excitement: infused T-cells expanded >3 log, the patient developed a cytokine-release syndrome (CRS) and tumor lysis syndrome (TLS), and achieved complete remission (CR); long-term persistence of CAR-T cells and persistent normal B-cell aplasia (a predictable, on-target effect when targeting CD19) were demonstrated.5Subsequent results in CLL have been heterogeneous; but in ALL and non-Hodgkin’s lymphoma (NHL), high CR rates have been noted across trials utilizing second generation CARs.1-4,12,14 However, the durability of response varies between studies, and has been difficult to determine since many patients subsequently proceeded to transplant...The use of lymphodepleting chemotherapy has been shown to enhance CAR T-cell expansion and persistence, and although the optimal drugs and schedule are unknown, review of published clinical trials across disease types suggest that the combination of fludarabine and cyclophosphamide may be most effective (Table 1).3,4,12Improvement in the toxicity profile of these agents is needed before broad adoption of this therapy can be recommended...Interestingly, detection of CAR T cells in the CSF did not correlate with development of neurologic toxicity in the study reported by Maude and colleagues.1Currently, the mainstay of CRS therapy is tocilizumab, an anti IL6 receptor antagonist, which results in prompt resolution of CRS-related symptoms in the majority of patients.20 Other IL6 inhibitors, such as siltuximab, a chimeric monoclonal antibody that binds to IL6, are under investigation...The CAR construct may be modified to include switch receptors that incorporate a part of the PD-1 receptor that result in increased PD-L1 expression in the tumor microenvironment, and paradoxically augment CAR T activity in solid tumors.30 In lymphoma, a clinical trial is underway combining the anti-PD-1 pembrolizumab with CD19 CAR (NCT02650999). Finally, the development of a third-party, “off-the-shelf” CAR would be a significant improvement for this technology. Pre-clinical studies showed the feasibility of the gene editing technique transcription activator-like effector nuclease (TALEN) to eliminate TCR alpha/beta, thus enabling the infusion of a third party CAR in a xenograft model without allo-reactivity; clinical trials with this technology are underway.31

Samples were matched for patient characteristics, treatment arm (capecitabine vs. 5-fluorouracil), and outcome based on recurrence-free survival (RFS) with 22 samples from patients who recurred and 22 samples from patients with durable RFS...In both tumor and stroma segments, over-expression of T cell activation markers (CD137, GITR) was associated with better outcome, whereas T cell markers (CD3, CD4, CD8) were not significantly associated with outcome... Using an in-depth analysis to precisely quantify the abundance of multiple immune function proteins in a spatially defined manner, we observed that PD-L2, IDO1, and T cell activation markers were robustly associated with durable RFS in both tumor and stromal segments. In contrast, MHC components (HLA-DR, beta-2-microglobulin), B cell markers (CD20), and NK cell markers (CD56) were strongly associated with favorable outcome in tumor but not in stromal segments. Our study highlights the conclusion that the immune landscape of TNBC is far too complex to be encompassed by any single molecular marker, and more detailed analyses of the DSP data reported here are ongoing with a view towards using quantitative multiplex analyses to refine our understanding of how therapeutic outcome is influenced by interactions among immune cells and between immune and tumor cells.