Anti-myeloma efficacy of CAR-iNKT is enhanced with a long-acting IL-7, rhIL-7-hyFc.

Multiple myeloma (MM), a malignancy of mature plasma cells, remains incurable. B-cell maturation antigen (BCMA) is the lead protein target for chimeric antigen receptor (CAR) therapy because of its high expression in most MM, with limited expression in other cell types, resulting in favorable on-target, off tumor toxicity. The response rate to autologous BCMA CAR-T therapy is high; however, it is not curative and is associated with risks of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome. Outcomes in patients treated with BCMA CAR-T cells (CAR-Ts) may improve with allogeneic CAR T-cell therapy, which offer higher cell fitness and reduced time to treatment. However, to prevent the risk of graft-versus-host disease (GVHD), allogenic BCMA CAR-Ts require genetic deletion of the T-cell receptor (TCR), which has potential for unexpected functional or phenotype changes. Invariant natural killer T cells (iNKTs) have an invariant TCR that does not cause GVHD and, as a result, can be used in an allogeneic setting without the need for TCR gene editing. We demonstrate significant anti-myeloma activity of BCMA CAR-iNKTs in a xenograft mouse model of myeloma. We found that a long-acting interleukin-7 (IL-7), rhIL-7-hyFc, significantly prolonged survival and reduced tumor burden in BCMA CAR-iNKT-treated mice in both primary and re-challenge settings. Furthermore, in CRS in vitro assays, CAR-iNKTs induced less IL-6 than CAR-Ts, suggesting a reduced likelihood of CAR-iNKT therapy to induce CRS in patients. These data suggest that BCMA CAR-iNKTs are potentially a safer, effective alternative to BCMA CAR-Ts and that BCMA CAR-iNKT efficacy is further potentiated with rhIL-7-hyFc.

Ventral striatum dopamine release encodes unique properties of visual stimuli in mice.

The mesolimbic dopamine system is an evolutionarily conserved set of brain circuits that play a role in attention, appetitive behavior, and reward processing. In this circuitry, ascending dopaminergic projections from the ventral midbrain innervate targets throughout the limbic forebrain, such as the ventral striatum/nucleus accumbens (NAc). Dopaminergic signaling in the NAc has been widely studied for its role in behavioral reinforcement, reward prediction error encoding, and motivational salience. Less well characterized is the role of dopaminergic neurotransmission in the response to surprising or alerting sensory events. To address this, we used the genetically encoded dopamine sensor dLight1 and fiber photometry to explore the ability of striatal dopamine release to encode the properties of salient sensory stimuli in mice, such as threatening looming discs. Here, we report that lateral NAc (LNAc) dopamine release encodes the rate and magnitude of environmental luminance changes rather than the visual stimulus threat level. This encoding is highly sensitive, as LNAc dopamine could be evoked by light intensities that were imperceptible to human experimenters. We also found that light-evoked dopamine responses are wavelength-dependent at low irradiances, independent of the circadian cycle, robust to previous exposure history, and involve multiple phototransduction pathways. Thus, we have further elaborated the mesolimbic dopamine system's ability to encode visual information in mice, which is likely relevant to a wide body of scientists employing light sources or optical methods in behavioral research involving rodents.