Chimeric antigen receptor T (CAR-T) cells are effective serial killers with a faster off-rate from dying tumor cells than CAR-T cells binding target cells through their T cell receptor (TCR). Here we explored the functional consequences of CAR-mediated signaling using a dual-specific CAR-T cell, where the same cell was triggered via TCR (tcrCTL) or CAR (carCTL). The carCTL immune synapse lacked distinct LFA-1 adhesion rings and was less reliant on LFA to form stable conjugates with target cells. carCTL receptors associated with the synapse were found to be disrupted and formed a convoluted multifocal pattern of Lck microclusters. Both proximal and distal receptor signaling pathways were induced more rapidly and subsequently decreased more rapidly in carCTL than in tcrCTL. The functional consequence of this rapid signaling in carCTL cells included faster lytic granule recruitment to the immune synapse, correlating with faster detachment of the CTL from the target cell. This study provides a mechanism for how CAR-T cells can debulk large tumor burden quickly and may contribute to further refinement of CAR design for enhancing the quality of signaling and programming of the T cell.

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Mucosal-associated invariant T (MAIT) cells are T cells that recognise vitamin-B derivative Ag presentedMultiple myeloma is a haematological malignancy characterised by a clonal outgrowth of malignant plasma cells in the bone marrow 1 . Advances in stem cell transplants and therapeutics over the last 15 years have seen major improvements in the long-term survival and quality of life of patients diagnosed with MM 2 , yet despite these advances, MM remains an incurable disease, with a median survival around 7 years 1 .The current treatment of MM is largely based on the doublet or triplet combinations of corticosteroids, proteasome inhibitors and/or immunomodulatory drugs (IMiDs) as induction therapy prior to autologous stem cell transplantation in younger patients. Lenalidomide (Len), is the most extensively used IMiD for the treatment of MM 3 . It has both direct anti-tumor and immune-mediated mechanisms of action through binding cereblon (CRBN), a component of an E3-ubiquitin ligase 4 . Len commonly forms the backbone of newly developed