A Phase I Study of Romidepsin in Combination With Gemcitabine, Oxaliplatin, and Dexamethasone in Patients With Relapsed or Refractory Aggressive Lymphomas Enriched for T-Cell Lymphomas.

Introduction: Histone deacetylase inhibitors (HDACi) and combination chemotherapy are independently used to treat relapsed/refractory (R/R) lymphoma. In vitro studies suggest that the addition of HDACi to platinum-based chemotherapy is synergistic.

Patients And Methods: We conducted a phase I study of romidepsin, gemcitabine, oxaliplatin and dexamethasone (Romi-GemOxD) in R/R aggressive lymphomas with an expansion cohort in T-cell lymphomas.

Nuclear EGFR in breast cancer suppresses NK cell recruitment and cytotoxicity.

Natural Killer (NK) cells can target and destroy cancer cells, yet tumor microenvironments typically suppress NK cell recruitment and cytotoxicity. The epidermal growth factor receptor (EGFR) is a potent oncogene that can activate survival, migration, and proliferation pathways, and clinical data suggests it may also play an immunomodulating role in cancers. Recent work has demonstrated a novel role for nuclear EGFR (nEGFR) in regulating transcriptional events unique from the kinase domain.

MicroRNA-146a deficiency enhances host protection against murine cytomegalovirus.

Natural killer (NK) cells are innate lymphoid cells that protect a host from viral infections and malignancies. MicroRNA-146a (miR-146a) is an important regulator of immune function that is highly expressed in NK cells and is further upregulated during murine cytomegalovirus (MCMV) infection. Here we utilized mice with a global targeted deletion of miR-146a to understand its impact on the innate immune responses to MCMV infection.

Cytokines drive the formation of memory-like NK cell subsets via epigenetic rewiring and transcriptional regulation.

Activation of natural killer (NK) cells with the cytokines interleukin-12 (IL-12), IL-15, and IL-18 induces their differentiation into memory-like (ML) NK cells; however, the underlying epigenetic and transcriptional mechanisms are unclear. By combining ATAC-seq, CITE-seq, and functional analyses, we discovered that IL-12/15/18 activation results in two main human NK fates: reprogramming into enriched memory-like (eML) NK cells or priming into effector conventional NK (effcNK) cells. eML NK cells had distinct transcriptional and epigenetic profiles and enhanced function, whereas effcNK cells resembled cytokine-primed cNK cells.

Memory-like differentiation enhances NK cell responses against colorectal cancer.

Metastatic (m) colorectal cancer (CRC) is an incurable disease with a poor prognosis and thus remains an unmet clinical need. Immune checkpoint blockade (ICB)-based immunotherapy is effective for mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRC patients, but it does not benefit the majority of mCRC patients. NK cells are innate lymphoid cells with potent effector responses against a variety of tumor cells but are frequently dysfunctional in cancer patients.

Single-cell T-cell receptor repertoire profiling in dogs.

Spontaneous cancers in companion dogs are robust models of human disease. Tracking tumor-specific immune responses in these models requires reagents to perform species-specific single cell T cell receptor sequencing (scTCRseq). scTCRseq and integration with scRNA data have not been demonstrated on companion dogs with cancer.

High-Dimensional Analyses Reveal IL15 Enhances Activation of Sipuleucel-T Lymphocyte Subsets and Reverses Immunoresistance.

Sipuleucel-T (sip-T) is the only FDA-approved autologous cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). To elucidate parameters of the response profile to this therapy, we report high-dimensional analyses of sip-T using cytometry by time of flight (CyTOF) and show a lymphoid predominance, with CD3+ T cells constituting the highest proportion (median ∼60%) of sip-T, followed by B cells, and natural killer (NK) and NKT cells. We hypothesized that treatment of sip-T with homeostatic cytokines known to activate/expand effector lymphocytes could augment efficacy against prostate tumors.

Engineering human pluripotent stem cell lines to evade xenogeneic transplantation barriers.

Successful allogeneic human pluripotent stem cell (hPSC)-derived therapies must overcome immunological rejection by the recipient. To build reagents to define these barriers, we genetically ablated β2M, TAP1, CIITA, CD74, MICA, and MICB to limit expression of HLA-I, HLA-II, and natural killer (NK) cell activating ligands in hPSCs. Transplantation of these cells that also expressed covalent single chain trimers of Qa1 and H2-K to inhibit NK cells and CD55, Crry, and CD59 to inhibit complement deposition led to persistent teratomas in wild-type mice.

Engineering Human Pluripotent Stem Cell Lines to Evade Xenogeneic Transplantation Barriers.

Allogeneic human pluripotent stem cell (hPSC)-derived cells and tissues for therapeutic transplantation must necessarily overcome immunological rejection by the recipient. To define these barriers and to create cells capable of evading rejection for preclinical testing in immunocompetent mouse models, we genetically ablated , , , , , and to limit expression of HLA-I, HLA-II, and natural killer cell activating ligands in hPSCs. Though these and even unedited hPSCs readily formed teratomas in cord blood-humanized immunodeficient mice, grafts were rapidly rejected by immunocompetent wild-type mice.

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.

T-BET and EOMES sustain mature human NK cell identity and antitumor function.

Since the T-box transcription factors (TFs) T-BET and EOMES are necessary for initiation of NK cell development, their ongoing requirement for mature NK cell homeostasis, function, and molecular programming remains unclear. To address this, T-BET and EOMES were deleted in unexpanded primary human NK cells using CRISPR/Cas9. Deleting these TFs compromised in vivo antitumor response of human NK cells.

Bendamustine/Rituximab Plus Cytarabine/Rituximab, With or Without Acalabrutinib, for the Initial Treatment of Transplant-Eligible Mantle Cell Lymphoma Patients: Pooled Data From Two Pilot Studies.

Introduction: Mantle cell lymphoma (MCL) is a moderately aggressive lymphoma subtype, generally viewed as incurable. For younger, fit patients, the standard of care remains various high-dose cytarabine-based induction regimens followed by autologous hematopoietic cell transplant and 3 years of rituximab maintenance. Despite reasonably good outcomes, with median progression-free survival in the range of 7 to 9 years, most patients eventually relapse, indicating a need to improve the safety and tolerability of remission induction strategies.

Costimulatory domains direct distinct fates of CAR-driven T-cell dysfunction.

T cells engineered to express chimeric antigen receptors (CARs) targeting CD19 have demonstrated impressive activity against relapsed or refractory B-cell cancers yet fail to induce durable remissions for nearly half of all patients treated. Enhancing the efficacy of this therapy requires detailed understanding of the molecular circuitry that restrains CAR-driven antitumor T-cell function. We developed and validated an in vitro model that drives T-cell dysfunction through chronic CAR activation and interrogated how CAR costimulatory domains, central components of CAR structure and function, contribute to T-cell failure.

Computational prediction of MHC anchor locations guides neoantigen identification and prioritization.

Neoantigens are tumor-specific peptide sequences resulting from sources such as somatic DNA mutations. Upon loading onto major histocompatibility complex (MHC) molecules, they can trigger recognition by T cells. Accurate neoantigen identification is thus critical for both designing cancer vaccines and predicting response to immunotherapies.