NKMax America Initiates Phase I Clinical Trial of SNK01-US01, an Autologous NK Cell Therapy for Refractory Cancers

On August 13, 2019, NKMax America, a biotechnology company developing NK (natural killer) cell therapies, announced the initiation of the Phase I clinical trial SNK01-US01 for SNK, an ex vivo expanded autologous NK cell therapy for the treatment of refractory cancers.

Paul Song, Chief Operating Officer of the company, stated, “We are pleased to launch the first clinical study of SNK in the United States and look forward to generating corresponding clinical data to support SNK as a safe and effective treatment option for patients with refractory cancer.”

Stephen Chen, MBA, Chief Technology Officer of NKMax America, commented, “Our manufacturing and provision of multi-dose NK cell immunotherapy drive us toward our goal of delivering transformative cancer treatments to patients.”

NK Cell Anti-Cancer Pathways

Natural killer (NK) cells are cytotoxic white blood cells that play a role in the innate immune system, serving as the first line of defense against dangerous infections or abnormal cells. As “first responders,” NK cells continuously patrol the body to seek out infected or abnormal cells. Upon encountering target cells, NK cells immediately recognize and initiate attacks, thereby rapidly and effectively identifying and destroying them.

NK cells attack target cells in two different ways:NK cells directly attach to target cells, triggering a cytotoxic cascade that leads to cell destruction; NK cells release small cytoplasmic granules containing perforin and proteases, which induce apoptosis in the target cells.NK cells also employ another mechanism by releasing cytokines into the bloodstream to recruit assistance from other types of immune cells; these cytokines send signals to B cells and T cells, triggering a broader immune response against target cells, whereby NK cells, together with other immune cells, attack and destroy the target cells.

NKMax’s SNK is an autologous therapy manufactured by harvesting a small amount of the patient’s immune cells. After harvest, NK cells are isolated from the blood, purified, activated, and expanded in cGMP facilities, and then the activated NK cells are reinfused into the patient to combat cancer.

In a single-arm, dose-escalation trial, SNK was administered intravenously once weekly for five weeks at three different doses to evaluate its safety and tolerability in adult patients with refractory cancer. The SNK study targeting refractory cancers is currently recruiting participants.

Applications of NK Cell Therapy in Cancer: Bispecific NK Cell TherapyOn June 24, NantKwest announced that the U.S. Food and Drug Administration (FDA) had approved its Investigational New Drug (IND) application for PD-L1 t-haNK, marking the first-in-human clinical trial of this agent in patients with locally advanced or metastatic solid tumors. Additionally, an earlier FDA approval was granted for a clinical trial using CD19 t-haNK, a bispecific engineered NK cell therapy, in patients with lymphoma. NantKwest is an immunotherapy company dedicated to treating cancer and virus-induced infectious diseases through NK cell-based therapies. PD-L1 t-haNK is an off-the-shelf bispecific NK cell therapy currently undergoing clinical trials in patients with solid tumors, targeting both PD-L1 and CD16. The company plans to combine various immunotherapeutic molecules with its proprietary, multi-targeted, off-the-shelf NK cell platform. PD-L1 t-haNK explores the unique therapeutic potential of integrating innate and adaptive immune systems to achieve durable complete responses. The company has established a leading portfolio of off-the-shelf NK cell candidates in clinical development, including three engineered NK-92 cell lines under investigation: haNK targeting CD16, t-haNK targeting CD19/CD16, and the current t-haNK targeting PD-L1/CD16.CAR-NK Cell Therapy Targeting CD19Researchers at MD Anderson Cancer Center are investigating CAR-NK cell therapy using umbilical cord blood-derived NK cells genetically modified to express a chimeric antigen receptor (CAR) that recognizes CD19. A clinical trial (NCT03056339), initiated in 2017, enrolls patients with relapsed disease. The institution is focusing on B-cell malignancies, including non-Hodgkin lymphoma as well as acute and chronic lymphocytic leukemia.CAR-NK Cell Therapy Targeting GPC3

In late 2017, NKGEN Biotech, in collaboration with the Shanghai Cancer Institute and Renji Hospital affiliated with Shanghai Jiao Tong University, published the first research paper on GPC3-targeted CAR-NK therapy for hepatocellular carcinoma in the prestigious medical journal Molecular Therapy. The results demonstrated that the GPC3-CAR-NK cell line (NK-92/9.28.z) could specifically target and kill GPC3-expressing hepatocellular carcinoma cells both in vitro and in vivo, without being affected by soluble GPC3 in serum, the hypoxic environment of solid tumors, or TGF-β. Compared to current CAR-T cell therapies, the CAR-GPC3-NK treatment regimen significantly reduces costs.

iPSC-Derived CAR-NK Cell Therapy

In a new study published in the journal Cell Stem Cell in June 2018, researchers from the University of California San Diego School of Medicine (UCSD) and the University of Minnesota reported that iPSC-derived CAR-NK cells exhibited activity similar to that of CAR-T cells, but with lower toxicity. The data indicated that ovarian cancer is a promising initial target, while solid tumors such as breast cancer, brain tumors, and colon cancer, as well as hematologic malignancies like leukemia, may also be potential therapeutic targets. NK cell therapy based on nicotinamide (NAM) technology

Gamida Cell has developed a nicotinamide (NAM)-based cell expansion technology for the generation of highly functional NK cells. Previous studies have demonstrated that, compared with conventional NK cells, NAM-NK cells exhibit faster proliferation, extended lifespan, and a superior capacity to produce inflammatory mediators and recruit other immune cells into tumors. Furthermore, when combined with targeting antibodies, NAM-NK cells display enhanced antibody-dependent cellular cytotoxicity (ADCC).

At this year’s American Society for Transplantation and Cellular Therapy (TCT) Annual Meeting, the company reported preliminary clinical data from a first-in-human trial of NAM-NK cell therapy using human leukocyte antigen (HLA)-haploidentical or HLA-mismatched related donors in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). Phase 1 study data showed that among the first 14 patients, three NHL patients and one MM patient achieved complete responses, and NAM-NK was generally well tolerated. The preliminary data support continued clinical development.

CytoSen’s proprietary nanoparticle processing technology, based on nanotechnology, enables the attachment of ligands that stimulate NK cell proliferation and activation onto nanoparticles. Treating NK cells with these nanoparticles enhances their ex vivo expansion and activation, supports multiple high-dose infusions, and exhibits potent anti-tumor cytotoxicity. The company’s lead NK cell candidate product, CSDT002-NK, underwent a proof-of-concept study in 25 patients at MD Anderson Cancer Center (MDACC). Preliminary results from the study showed a relapse rate of 8% and a progression-free survival (PFS) rate of 66%.

Conclusion

As scientists continue to explore the anticancer potential of NK cells, NK cell therapy is poised to become as widely used in cancer treatment as T cell therapy in the future, with growing optimism from both enterprises and cancer patients regarding its prospects.

References

https://www.biospace.com/article/releases/nkmax-america-doses-first-subject-in-phase-i-trial-of-snk-in-patients-with-refractory-cancer/

https://www.gamidacell.com/namtechnology/

https://www.clinicaltrials.gov/ct2/show/NCT03941262

https://www.nkmaxamerica.com/