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More about CAR NK cells
Natural killer (NK) cells engineered to express interleukin-21 (IL-21) demonstrated sustained antitumor activity against glioblastoma stem cell-like cells (GSCs) both in vitro and in vivo, according to new research from The University of Texas MD Anderson Cancer Center.
The preclinical findings, published today in Cancer Cell, represent the first evidence that engineering NK cells, a type of innate immune cell, to secrete IL-21 resulted in strong activity against glioblastoma, a cancer type in need of more effective treatment options.
“Our research uncovered a previously unknown mechanism that plays an important role in NK cell memory against glioblastoma, highlighting the potential of NK cells engineered to express IL-21 in treating this disease,” said Katy Rezvani, M.D., Ph.D., professor of Stem Cell Transplantation & Cellular Therapy. “The ability of these IL-21 engineered natural killer cells to recognize and kill glioblastoma stem cell-like cells offers a highly promising therapeutic approach.”
Glioblastoma is an aggressive brain cancer with limited therapeutic options. Current treatment options for glioblastoma include surgery, radiation therapy and chemotherapy, but these options offer limited efficacy and patients have a median survival of just 18 to 21 months. According to the National Brain Tumor Society, the five-year survival rate for patients with glioblastoma is only 6.9%, with an average estimated length of survival of only eight months.
As part of the innate immune system, NK cells have a natural ability to recognize and eliminate GSCs. Engineering these cells can boost their fitness and antitumor activity. IL-21 is an immune signaling protein, or cytokine, shown to promote better metabolic fitness in NK cells.
In this study, first author Mayra Shanley, Ph.D., principal research scientist at MD Anderson, and her co-authors used multiple in vitro and in vivo models to treat GSCs with NK cells engineered to express either IL-21 or IL-15, another cytokine used to boost NK cell activity.
While both groups of engineered NK cells displayed strong activity against GSCs in vitro, the IL-21 NK cells exhibited a stronger metabolic fitness than those expressing IL-15. Previous research by MD Anderson researchers identified lost metabolic fitness as a key mechanism in tumor resistance.
In vivo, the IL-21 NK cells showed limited toxicity and excellent tumor control in murine models of patient-derived GSC, compared to high toxicity and ineffective tumor control with IL-15 NK cells, which became exhausted over time.
Researchers also identified the CCAAT/Enhancer-Binding Protein (C/EBP), particularly CEBPD, as a critical transcription factor that plays an important role in regulating the sustained anti-GSC cytotoxicity of IL-21 NK cells. When CEBPD was deleted, the potency of IL-21 NK cells decreased, while overexpression of CEBPD in NK cells increased their long-term cytotoxicity, metabolic fitness and anti-GSC potency in vivo. This enhanced activity was linked to distinct transcriptional and epigenetic signatures compared to IL-15 NK cells.
Based on these findings, researchers at MD Anderson will begin investigating the clinical application of IL-21 engineered NK cells in patients with glioblastoma, with a trial anticipated to begin later this year.
A full list of collaborating authors and their disclosures can be found with the full paper here. The research was supported by Ann and Clarence Cazalot, Jr., the Sally Cooper Murray Chair in Cancer Research, MD Anderson’s Glioblastoma Moon Shot®, the National Institutes of Health (NIH) (U01CA247760, P50CA127001, CA016672, 1S10OD024977-01), and the Cancer Prevention and Research Institute of Texas (CPRIT) (RP180684).
Adding CD28 costimulation to cord blood-derived chimeric antigen receptor (CAR) natural killer (NK) cells targeting CD70+ cancers significantly enhanced antitumor efficacy and long-term cytotoxicity of the CAR NK cells, according to researchers from The University of Texas MD Anderson Cancer Center.
The findings, published today in Cancer Discovery, demonstrate that the addition of CD28, a T cell centric costimulatory molecule that is normally absent in mature NK cells, can enhance CAR NK function in preclinical models of hematologic cancers and solid tumor malignancies, suggesting this engineering approach should be considered for future NK cell therapies.
“Based on the innate anti-tumor activity of NK cells against cancer and the potential of CD70 as a target antigen, CD70-targeting CAR NK cells hold significant promise as effective treatment for many solid tumors,” said senior author Katy Rezvani, M.D., Ph.D., professor of Stem Cell Transplantation & Cellular Therapy. “After exploring multiple costimulatory molecules, we found that adding CD28 was a worthwhile approach to improving the cells’ persistence and efficacy, suggesting the potential for strong outcomes.”
CD70 expression has been shown to contribute to tumor progression and immune evasion, making it an ideal target for CAR NK cell therapy. Therefore, researchers led by Sunil Acharya, Ph.D., principal research scientist in the Rezvani lab, sought to engineer and optimize CD70-targeting CAR NK cells for use as cancer cell therapies.
To accomplish this, they incorporated CD27, the natural receptor for CD70, into the CAR NK cells to bind CD70+ cancer cells. They also evaluated various costimulatory molecules, including CD28, paired with CD3ζ to enhance CAR NK cell activity. Finally, the cells also included IL-15 to improve NK cell persistence and iC9 as a safety switch, based on previous research findings.
The CAR NK cells with CD28 demonstrated high cytotoxicity against CD70+ tumor cells in vitro and in multiple tumor models of hematologic and solid tumors. CD28 consistently emerged as one of the top costimulatory molecules tested. After a closer look, the researchers discovered that CD28 activates key signaling pathways involving LCK, CD3ζ and ZAP70 in the CAR NK cells to enhance their anti-tumor activity.
Based on these results, researchers at MD Anderson have initiated first-in-human Phase I/II clinical studies to assess the safety and efficacy of CAR27 NK cells with C28 in patients with CD70+ hematologic malignancies (NCT05092451) and solid cancers (NCT05703854).
A full list of collaborating authors and their disclosures can be found with the full paper here. The research was supported by MD Anderson’s Moon Shots Program® and its adoptive cell therapy platform, the Sally Cooper Murray Endowed Chair in Cancer Research, the National Institutes of Health (NIH) (1 R01 CA211044-01, R01GM143243, 5 P01CA148600-03, U01CA247760, P50CA100632, CA016672, P30CA016672, P30 CA125123), the Cancer Prevention and Research Institute of Texas (CPRIT) (RP180466, RP210227), Stand Up To Cancer Dream Team Research, and the Leukemia Specialized Program of Research Excellence (SPORE) (P50CA100632).
Researchers from The University of Texas MD Anderson Cancer Center reported promising results in a Phase I/II trial of 37 patients with relapsed or refractory B-cell malignancies who were treated with cord blood-derived chimeric antigen receptor (CAR) natural killer (NK) cell therapy targeting CD19.
Published today in Nature Medicine, the findings reveal an overall response (OR) rate of 48.6% at 100 days post treatment, with one-year progression-free survival (PFS) and overall survival (OS) rates of 32% & 68%, respectively. The trial reported an excellent safety profile with no cases of severe cytokine release syndrome (CRS), neurotoxicity, or graft-versus-host disease.
Another key discovery of the trial was the importance of the selection criteria for allogeneic cord blood donors in CAR NK cell manufacturing. Cord blood units that were cryopreserved within 24 hours of collection and those with a low nucleated red blood cell content were associated with markedly better outcomes. CAR NK cells generated from these units resulted in a one-year PFS rate of 69% and an OS rate of 94%, compared to 5% and 48%, respectively, from those units with higher nucleated red blood cell content or longer collection-to-cryopreservation times.
“The responses observed in these patients are very encouraging as we continue to evaluate the long-term efficacy of CAR NK cells in the treatment of these malignancies,” said senior author Katy Rezvani, M.D., Ph.D., professor of Stem Cell Transplantation & Cellular Therapy. “In order to have a successful allogeneic cell therapy, it is also critical that we identify the characteristics of an optimal allogeneic donor for CAR NK manufacturing. We were able to identify two key factors associated with cord blood units most likely to yield a positive clinical response and discerned the biologic mechanisms underlying this phenomenon.”
The study also noted encouraging response rates across different types of B-cell malignancies. The OR rate at 30 days post treatment was 100% for patients with low-grade non-Hodgkin lymphoma (NHL), 67% for those with chronic lymphocytic leukemia (CLL) without transformation and 41% in patients with diffuse large B-cell lymphoma (DLBCL).
Researchers also observed durable responses with CAR NK cell treatment. One year after treatment, complete responses were seen in 83% of patients with low grade-NHL, 50% of patients with CLL and 29% of patients with DLBCL. Those with a response at 30 days post treatment were significantly more likely to have PFS at one-year after treatment.
These results build on previous data from this trial, published in the New England Journal of Medicine, demonstrating that a single infusion of CAR NK cells achieved remission in 73% of a smaller cohort of patients with B-cell malignancies.
“Our study stresses the importance of identifying donor-specific predictors of response after allogeneic cell therapy, especially since one donor may be used to treat hundreds of patients. CAR NK cells have the potential to be manufactured in advance and stored for off-the-shelf immediate use,” Rezvani said. “This could potentially increase patient access to these cell therapies, reduce treatment time and lower cost of therapy.”
The selection criteria identified in this study are being applied to select donors for ongoing and future trials at MD Anderson with engineered cord blood NK cells at MD Anderson, extending the platform to target other antigens and malignancies, including solid tumors.
This research was supported by MD Anderson’s Moon Shots Program®, the Sally Cooper Murray Endowed Chair in Cancer Research, the National Institutes of Health (NIH) (1 R01CA211044-01, 5 P01CA148600-03, P50CA100632, CA016672), the Cancer Prevention and Research Institute of Texas (CPRIT) (RP180466) and Stand Up To Cancer. A complete list of collaborating authors and their disclosures can be found with the full paper here.
Disclosure
MD Anderson’s CAR NK cell therapy platform was licensed to Takeda in 2019, and MD Anderson has implemented an Institutional Conflict of Interest Management and Monitoring Plan for this research. Takeda’s investigational cryopreserved CD19-targeted CAR NK therapy (TAK-007), currently in Phase II clinical development, is of a distinct formulation from the cell therapy being developed by MD Anderson and described in this manuscript.
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Katy Rezvani, M.D., Ph.D., professor of Stem Cell Transplantation & Cellular Therapy at The University of Texas MD Anderson Cancer Center, has been honored with the E. Donnall Thomas Lecture and Prize from the American Society of Hematology (ASH) for her groundbreaking research to develop and advance innovative cell therapies for cancer using natural killer (NK) cells.
A new study led by researchers at The University of Texas MD Anderson Cancer Center discovered loss of metabolic fitness in chimeric antigen receptor (CAR) natural killer (NK) cells is a critical mechanism of resistance, with infused cells gradually losing the ability to compete with tumor cells for nutrients, leading to tumor relapse.
The study, published today in Science Advances, demonstrates that engineering CAR NK cells to express interleukin-15 (IL-15) enhances the cells’ metabolic fitness and provides a longer-lasting anti-tumor response. In addition, two infusions of CAR NK cells expressing IL-15 boosted survival in comparison to a single dose.
The collaborative research was led by co-corresponding authors Ken Chen, Ph.D., professor of Bioinformatics and Computational Biology, and Katy Rezvani, M.D., Ph.D., professor of Stem Cell Transplantation & Cellular Therapy, along with researchers in the Chen and Rezvani labs.
“Understanding the mechanism of resistance facilitates more focused interrogation to identify strategies by which we can mitigate or circumvent these resistance mechanisms and improve efficacy of the CAR NK cell therapy,” Chen said.
As part of the preclinical study, researchers focused on genetically engineered NK cells with a CAR targeting the CD19 tumor antigen (CAR19). Using laboratory models of lymphoma, they evaluated cells that expressed either CAR19 alone, IL-15 alone, or both CAR19 and IL-15 to investigate the ability of IL-15 to activate NK cells and to enhance their potency and persistence.
Researchers observed the emergence of NK cell clusters with distinct patterns of activation, function and metabolic signature associated with different phases of in vivo evolution and tumor control. Interactions with the highly metabolically active tumor resulted in loss of metabolic fitness in NK cells that was partly overcome with the expression of IL-15.
To overcome this resistance, mice received a second infusion of CAR19/IL-15 NK cells 14 days after the first. The second infusion increased the number of functional NK cells and resulted in long-term tumor eradication.
The relevance of the preclinical findings were confirmed in samples from two patients with lymphoid malignancies treated with CAR19/IL-15 NK cells as part of a recent clinical trial.
“Our data suggest that successful treatment using CAR NK cells may require multiple infusions in order to achieve a robust NK cell population capable of mounting a strong anti-tumor response, especially for difficult to treat and highly metabolically active tumors,” Rezvani said.
The increase in functional NK cells with a second infusion provides researchers with a clinically actionable strategy to improve efficacy of CAR NK cell therapy and warrants further investigation. Researchers will continue to validate their findings in additional tumor models and study mechanisms of resistance in upcoming clinical trials with CAR NK cells targeting CD70 in solid tumors.
A full list of collaborating authors and their disclosures can be found with the full paper here. The research was supported in part by MD Anderson’s Moon Shots Program® and its adoptive cell therapy platform. Additional support includes the Sally Cooper Murray Chair in Cancer Research, the National Institutes of Health (1 R01 CA211044-01, 5 P01CA148600-03, U01CA247760, P50CA100632, P30CA016672), the Cancer Prevention and Research Institute of Texas (RP180466, RP180248), and the Chan Zuckerberg Initiative.