Adoptive Immunotherapy With Universal Allogeneic Natural Killer Cells

Technology Overview

Dr. Colleen S. Delaney

Natural killer (NK) cells are among the first responders of the immune system. These cells have multiple functions in the defense against cells that are pathogenic due to viral infection or malignancy. NK cells secrete cytotoxins to selectively kill pathogenic cells and cytokines to coordinate the actions of other immune cells. NK cells can be engineered to be immunotherapy agents and express chimeric antigen receptors (CARs) against markers of infectious disease or cancer.

CAR-NK cells have distinct advantages over CAR T cells used for immunotherapy. Allogeneic CAR-NK cells do not require donor-recipient HLA compatibility and do not cause graft-versus-host disease (GVHD). In addition, CAR-NK cells do not overproliferate and release toxic levels of cytokines when activated, which eliminates the serious complications of many therapeutic CAR T cells such as neurotoxicity and cytokine release syndrome. The ability to treat patients without the need for HLA matching paves the way for off-the-shelf, on-demand clinical use of cryopreserved CAR-NK cells. However, CAR-NK cells are more challenging to generate than CAR T cells because NK cells are more sensitive to the genetic materials used in cell engineering.

Stem cell transplantation physician Colleen Delaney, MD, MSc, has the expertise to engineer NK cells. She led development of a low-cost, standardized, highly scalable system for producing clinically available NK cells from stem cells in umbilical cord blood. These undifferentiated cells arise from healthy donors and have low risk of exposure to external toxins and infectious agents. This work draws on Dr. Delaney’s decades of experience working with hematopoietic stem cells and treating patients.

Engineering NK cells

The rapid generation of activated NK cells begins by pooling donor cord blood cells carrying the CD34 marker of hematopoietic stem cells. The Delaney Lab uses a proprietary protocol to first expand and then differentiate the cells into mature and active NK cells, bypassing costly, time-consuming proliferation and activation culture processes with feeder cells. Unlike autologous therapeutic cells, which treat only the single patient from whom they are derived, allogeneic cells can treat any patient. With Dr. Delaney’s system, repeated dosing is easy and inexpensive, as hundreds of vials of cryopreserved, ready-to-use cells can be generated for a few thousand dollars per dose.

Dr. Delaney and colleagues demonstrated the safety and potential efficacy of their off-the-shelf allogeneic NK cells in two phase 1 clinical trials, one for COVID-19 and the other for acute myeloid leukemia (AML). Their investigator-initiated trials quickly generated NK cells that were shown to be safe for patients.

The Delaney Lab can go from cord blood cells to clinically accessible, targeted CAR-NK cells in as little as 3 weeks. To generate CAR-NK cells, genes of interest are introduced early in the stem cell expansion process, when the cell pool is small and more receptive to genetic modifications, reducing the costs of viral transduction. The researchers can also generate NK cells that secrete cytokines to armor the CAR-NK cells against functional exhaustion and extend their persistence, which increases their effectiveness.

Among the multiple clinical applications for CAR-NK cells are treatments for blood cancers. The Delaney Lab has evidence supporting the efficacy of dual-targeting CD19/CD72 CAR-NK cells. CD72 is a target for B-cell malignancies, so combining it with CD19 helps prevent antigen escape and relapse, which is common with CD19 CAR T-cell therapy. To overcome the challenge of hematological cancer relapse, the Delaney Lab is creating CAR-NK cells expressing CXCR4 and CXCR5, which localize the cells to bone marrow and lymph nodes. At these sites, the CAR-NK cells target residual and circulating cancerous cells. Additionally, CXCR4-expressing CAR-NK cells have potential applications in preventing tumor metastasis and angiogenesis.

Among solid tumor targets, the Delaney Lab is creating CAR-NK cells against STEAP1, a tumor antigen in Ewing sarcoma and some prostate, colon, bladder and lung cancers. Another solid tumor target is GD2, which is a marker on neuroblastomas, glioblastomas, neuroendocrine tumors and melanomas.

Dr. Delaney is a founder and leader of two cell therapy companies to date, Deverra Therapeutics and Nohla Therapeutics, raising more than $175 million in funding for them. Dr. Delaney can quickly generate NK cells expressing a gene of interest for an industry partner. She is interested in collaborations that advance and apply her platform for low-cost, ex vivo generation of unmodified NK cells and CAR-NK cells for immunotherapy.

Stage of Development

• Preclinical in vitro
• Preclinical ex vivo
• Preclinical in vivo
• Investigator-initiated clinical trials

Partnering Opportunities

• Collaborative research and development
• Sponsored research agreement
• Consultation agreement
• Custom CAR-NK cell generation
• Licensing agreement
• Clinical trials
• Investor-initiated clinical trials

Learn More

• Colleen S. Delaney, MD, MSc
• Solid Tumors – Off-the-Shelf Immunotherapies

Publications

1. Liu WL, Kampouri E, Bui JK, Delaney CS, et al. Off-the-shelf allogeneic natural killer cells for the treatment of COVID-19. Mol Ther Methods Clin Dev. 2024;32(4):101361.
2. Hsieh E, Jamison B, Brempelis K, Delaney C, et al. Abstract 32: Engineering cord blood CD34+ cells for the generation of allogeneic NK or myeloid cell immunotherapies. Stem Cells Transl Med. 2024;13(Suppl 1):S36.
3. Shi PA, Luchsinger LL, Greally JM, Delaney CS. Umbilical cord blood: an undervalued and underutilized resource in allogeneic hematopoietic stem cell transplant and novel cell therapy applications. Curr Opin Hematol. 2022;29(6):317-326.
4. Dahlberg A, Woo S, Delaney C, et al. Notch-mediated expansion of cord blood progenitors: maintenance of transcriptional and epigenetic fidelity. Leukemia. 2015;29(9):1948-51.

Last updated June 2026