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Natural Killer Cell and Lymphocyte-Targeted Immunotherapies in Cancer

The "Natural Killer Cell and Lymphocyte-Targeted Immunotherapies in Cancer" study is an umbrella repository for data pertaining to multiple clinical trials that aim to assess NK cell and lymphocyte-targeted immunotherapy strategies across cancer types. Here, data from three trials, NCT03068819, NCT02782546, and NCT03687957 are presented.

Cytokine Induced Memory-like NK Cell Adoptive Therapy for Relapsed AML after Allogeneic Hematopoietic Cell Transplant in Children and Adults (NCT03068819)

Pediatric and young adult (YA) patients with acute myeloid leukemia (AML) who relapse after allogeneic hematopoietic cell transplantation (HCT) have extremely poor prognosis. Standard salvage chemotherapy and donor lymphocyte infusions (DLI) have little curative potential. Previous studies showed that natural killer (NK) cells can be stimulated ex vivo with interleukin-12 (IL-12), IL-15, and IL-18 to generate memory-like (ML) NK cells with enhanced anti-leukemia responses. We treated nine pediatric/YA patients with post-HCT relapsed AML with donor ML NK cells on a phase I trial. Patients received fludarabine, cytarabine, and filgrastim followed two weeks later by infusion of DLI and ML NK cells from the original HCT donor. ML NK cells were successfully generated from haploidentical, matched-related and matched-unrelated donors. Following infusion, donor-derived ML NK cells expanded and maintained ML multidimensional mass cytometry phenotype for over 3 months. Furthermore, ML NK cells exhibited persistent functional responses as evidenced by leukemia-triggered IFN-gamma production. Following DLI and ML NK cell adoptive transfer, 4 of 8 evaluable patients achieved complete remission at day 28. Two patients maintained a durable remission for over 3 months with one patient in remission for greater than two years. No significant toxicity was experienced. This study demonstrates that in a compatible immune environment post-HCT, donor ML NK cells robustly expand and persist with potent anti-leukemic activity in the absence of exogenous cytokines. ML NK cells in combination with DLI present a novel immunotherapy platform for AML that has relapsed after allogeneic HCT. This trial was registered at https://www.clinicaltrials.gov/study/NCT03068819.

A Phase II Study of Cytokine Induced Memory-like NK Cell Adoptive Therapy after Haploidentical Donor Hematopoietic Cell Transplantation (NCT02782546)

Natural killer (NK) cells are innate lymphoid cells that eliminate cancer cells, produce cytokines, and are being investigated as a nascent cellular immunotherapy. Impaired NK cell function, expansion, and persistence remain key challenges for optimal clinical translation. One promising strategy to overcome these challenges is cytokine-induced memory-like (ML) differentiation, whereby NK cells acquire enhanced anti-tumor function following stimulation with IL-12, IL-15, and IL-18. Here, reduced-intensity conditioning (RIC) for HLA-haploidentical hematopoietic cell transplantation (HCT) was augmented with same-donor ML NK cells on Day 7 and 3 weeks of N-803 (IL-15 superagonist) to treat patients with relapsed/refractory acute myeloid leukemia (AML) in the clinical trial (NCT02782546). In 15 patients, donor ML NK cells were well-tolerated and 87% of patients achieved a composite complete response at Day 28, which corresponded with clearing high-risk mutations, including TP53 variants. NK cells were the major blood lymphocytes for two months post-HCT with prolific expansion (1104-fold) over 1-2 weeks. Multidimensional mass cytometry and CITE-seq identified donor ML NK cells as distinct from conventional NK cells and persisting for over two months. ML NK cells expressed CD16, CD57, and high granzyme B and perforin, along with a unique transcription factor profile. ML NK cells differentiated in patients had enhanced ex vivo function compared to conventional NK cells from both patient and healthy donors. Overall, same-donor ML NK cell therapy with 3 weeks of N-803 support safely augmented RIC haplo-HCT for AML, with ML NK cells demonstrating enhanced in vivo persistence and functionality, overcoming barriers in the field.

NT-I7, a long-acting interleukin-7, increases lymphocyte counts and induces CD8+ T cell clonotype expansion in patients with newly diagnosed high-grade gliomas (NCT03687957)

Patients with high-grade gliomas (HGG), including glioblastoma (GBM), face a poor prognosis despite standard-of-care maximal surgical resection followed by concurrent radiation therapy (RT) and temozolomide (TMZ). Adjuvant chemoradiation frequently induces severe treatment-related lymphopenia (TRL) in over 40% of patients, which is associated with early tumor progression and decreased overall survival. Paradoxically, patients with HGG exhibit abnormally low levels of interleukin-7 (IL-7) following chemoradiation, impairing the homeostatic recovery of T cells. NT-I7 (efineptakin alfa) is a bioengineered long-acting IL-7 analog consisting of recombinant human IL-7 fused to a hybrid Fc region, which ameliorates treatment-related cytopenia and enhances cytotoxic CD8+ T cell abundance in preclinical glioma models. We conducted a Phase I dose-escalation trial (NCT03687957) to determine the maximum tolerated dose (MTD) of NT-I7 and evaluate its effects on absolute lymphocyte counts (ALC) and lymphocyte subsets in patients with newly diagnosed HGG following standard concurrent chemoradiation. Comprehensive immune profiling of peripheral blood, including single-cell RNA sequencing (scRNA-seq), was performed to characterize the immunological effects of NT-I7 in vivo. These findings have implications for combining NT-I7 with immune-based therapies such as checkpoint inhibitors, CAR-T cells, or cancer vaccines in primary brain tumors. This trial was registered at https://www.clinicaltrials.gov/study/NCT03687957.