Dwivedi et al. Page 846

Chimeric antigen receptor (CAR) T cell therap. has shown great efficacy against CD19 positive hematological cancers. However, cytokine release syndrome (CRS) in patients treated with CD19 CAR-T cell therapy remains a significant toxicity to address. Dwivedi and colleagues developed a novel anti-CD19 CAR T cell containing a humanized framework region of scFv from a murine FMC63 monoclonal antibody. The humanized CAR T cell released significantly less cytokines (IFN-γ, TNF-α), reduced IL-6 induction from monocytes, and produced a more even CD4+ and CD8+ T cell distribution. Furthermore, CAR T cells eradicated NALM6 tumor burden in vivo. Taken together, these modified features might be beneficial for reducing toxicity of CAR T cells.

Branch et al. Page 763

Mutations occurring in the ligand binding domain of the androgen receptor (AR) lead to therapy resistance. In particular, the AR F877L mutation leads to an antagonist-to-agonist switch in response to second-generation inhibitors such as enzalutamide and apalutamide. Branch and colleagues describe JNJ-63576253, a next-generation AR pathway inhibitor of wild-type, AR F877L, and other clinically detected ligand binding domain mutants. JNJ-63576253 inhibited downstream target gene expression of AR and impeded tumor growth in an enzalutamide-resistant F887L xenograft model. Their results support the ongoing Phase 2 clinical development of JNJ-63576253 (NCT02987829).

Corbellari et al. Page 859

IL-2 and IL-15 are both able to stimulate the proliferation of T cells, promote the synthesis of immunoglobulin, and preserve the survival of NK cells. However, IL-2 also maintains peripheral regulatory T cells (Tregs), while IL-15 instead stimulates the survival of CD8+ memory T cells. In this manuscript, Corbellari and colleagues describe two IL-15-diabody fusions with the F8 antibody (F8-F8-IL-15 and F8-F8-SD-IL-15). These antibody-interleukin-15 fusion proteins showed favorable distribution profiles and displayed potent anti-cancer activity in a mouse model of lung metastasis. These studies reinforce the many clinical studies investigating the use of targeted IL-15 therapies.

Greenman et al. Page 872 and Page 946

In two related manuscripts Greenman, Pizam, and colleagues performed an extensive study of the functional significance of the biophysical properties of chimeric antigen receptor engineered T cells (CAR T cells). They generated an experimental system in which affinity, avidity and antigen density are controllable within a single experimental model of a specific HLA-peptide complex targeted with TCR-like antibodies of single defined specificity. In the second manuscript they built an evolving phenotypic model of CAR T-cell regulation, which suggested that receptor down-modulation is a key determinant of CAR T-cell function. These results have a potential to predict and therefore advance the rational design of CAR T-cell therapy.