Will CAR-NK Cancer Therapy Surpass High-Cost CAR-T Immunotherapy?

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Will CAR-NK Cancer Therapy Surpass High-Cost CAR-T Immunotherapy?

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Will CAR-NK Cancer Therapy Surpass High-Cost CAR-T Immunotherapy?

Breakthrough in Affordable and Effective Cancer Treatment – CAR-NK Therapy Shows Promise to Surpass High-Cost CAR-T.

In a major development presented at the 2023 European Hematology Association (EHA) Congress, preliminary data from the phase 1 trial (NCT05020678) of NKX019 were unveiled.

NKX019, a cryopreserved CD19-targeted allogeneic CAR-NK cell therapy, demonstrates potential for treating B-cell malignancies.

The study enrolled 19 patients with relapsed or refractory CD19-positive B-cell malignancies, with a median age of 59 and ECOG performance status of 0 or 1, who had previously undergone at least two treatments.

During the treatment process, patients underwent lymphodepletion (cyclophosphamide + fludarabine) before receiving NKX019 therapy.

Results revealed an overall response rate of 80% in the evaluable patients (n=10), with a complete response (CR) rate of 70%.

Notably, the CR rate for large B-cell lymphoma (LBCL) patients was 50%, marking a groundbreaking advancement and bringing the emerging star, “CAR-NK cells,” into the spotlight.

What is CAR-NK Therapy?

CAR-NK cells, or chimeric antigen receptor-natural killer (CAR-NK) cells, are designed to mimic CAR-T cells.

Through genetic engineering, the synthetic CAR structure is transcribed into NK cells, essentially equipping them with a “GPS” device.

This allows NK cells to retain their original functions while precisely targeting specific antigen proteins, making cancer cells unable to escape.

Pros and Cons of CAR-T and NK Cell Therapies:

1. CAR-T Cells – Expensive Cancer “Star Products”

CAR-T cell therapy has gained prominence in cancer immunotherapy, reprogramming patients’ own T cells with a DNA segment encoding CAR. While it has shown significant success in treating hematologic tumors, such as acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and B-cell lymphomas, its complex and lengthy manufacturing process and potential adverse reactions, such as cytokine release syndrome, hinder widespread clinical use.

2. NK Cells – Immune “Lieutenants” in Cancer Defense

NK cells, or natural killer cells, play a crucial role in the innate immune response against pathogens and cancer cells. They do not require prior sensitization and act as frontline defenders in cancer immunity. Despite limitations, such as low prevalence in the body and short-lasting efficacy post-infusion, NK cells are considered ideal for adoptive immunotherapy.

Advantages of CAR-NK Therapy

1. Enhanced Anti-Cancer Effectiveness CAR-NK cells act as both frontline warriors and collaborators with T cells, yielding superior anti-cancer effects. NK cells rapidly release cytotoxic granules to attack tumor cells without antigen presentation, complementing the T-cell recognition of tumor antigens through the activated CAR pathway.

2. Prevention of Immune Escape Unlike CAR-T cells, CAR-NK cells maintain intrinsic targeting capabilities through natural receptors, making it difficult for cancer cells to escape by downregulating CAR-targeted antigens, thus preventing tumor escape events.

3. Reduced Side Effects CAR-NK cells have broader sourcing options, allowing for autologous or allogeneic use without significant adverse reactions like graft-versus-host disease, cytokine release syndrome, or neurotoxicity, resulting in a safer treatment option.

4. Higher Practicality CAR-NK cells do not induce graft-versus-host disease, eliminating the need for patient matching. This enables the production of multiple “off-the-shelf” CAR-NK cell products from a single donor, significantly reducing treatment time and costs compared to CAR-T cells.

CAR-NK Shining in Blood Cancer Treatment

Similar to CAR-T therapy, CAR-NK therapy initially targeted hematologic malignancies, including leukemia, myeloma, and lymphoma. Clinical trials have shown CAR-NK’s sensitivity to multiple myeloma, effective lysis of leukemia malignant cells through CD19-targeted CAR-NK cells, particularly in B-cell malignancies.

A clinical trial at MD Anderson Cancer Center demonstrated a 73% overall response rate, with 64% achieving complete remission in patients with relapsed or refractory B-cell hematologic malignancies after CAR-NK cell infusion.

CAR-NK Making Strides in Solid Tumor Treatment

Several studies confirm the feasibility of CAR-NK cells in treating solid tumors, such as ovarian, breast, pancreatic, colorectal, glioblastoma, liver, and head and neck cancers. Notable developments include:

NK010 Injection – Overcoming Ovarian Cancer and Acute Myeloid Leukemia In June 2023, data from clinical trials of China-developed non-genetically modified peripheral blood-derived NK010 injection were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting. The treatment showed promise in managing platinum-resistant or platinum-refractory advanced ovarian cancer and refractory/relapsed acute myeloid leukemia (AML).

Results revealed disease stability in the low-dose group and one middle-dose patient after two treatment cycles. In the low-dose group, continued treatment led to partial remission after the third cycle. Notably, the best response included a 60% reduction in lesion size among patients continuing treatment. No severe adverse reactions, such as cytokine release syndrome or graft-versus-host disease, were reported during the trial.

FT536 Clinical Trial FDA Approval – Targeting Various Solid Tumors On January 10, 2022, the U.S. FDA approved the Investigational New Drug (IND) application for FT536, an innovative CAR-NK therapy. Engineered from induced pluripotent stem cells (iPSC), FT536 is a “ready-to-use” CAR-NK cell therapy with multiple modifications. It primarily targets various solid tumors, including breast, ovarian, pancreatic, gastric, advanced non-small cell lung, colorectal, and head and neck cancers.

Closing Thoughts

The advent of CAR engineering has revolutionized the field of cell therapy, with CAR-T laying the foundation for immunotherapy. Despite its drawbacks, CAR-T research has inspired investigations into other immune effector cells.

NK cells, possessing innate immune characteristics, hold great promise for cancer treatment post-CAR modification. CAR-NK cells, with their potential for clinical translation and industrial-scale production, offer hope for a broader spectrum of cancer patients. Future advancements may witness the integration of more technologies with CAR engineering to enhance immune effector cell functionality, overcoming additional malignant tumors.

Will CAR-NK Cancer Therapy Surpass High-Cost CAR-T Immunotherapy?

References:

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[1]Zhang L,et al.CAR-NK cells for cancer immunotherapy: From bench to bedside[J]. Biomarker Research,2022, 10(1): 1-19.

https://biomarkerres.biomedcentral.com/articles/10.1186/s40364-022-00364-6

[2]Li H,et al.Preclinical and clinical studies of CAR-NK-cell therapies for malignancies. Front Immunol. 2022 Oct 24;13:992232. doi: 10.3389/fimmu.2022.992232.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9637940/

[3]Daher M,et al.CAR-NK cells: the next wave of cellular therapy for cancer. Clin Transl Immunol 10: e1274[J]. 2021.

https://onlinelibrary.wiley.com/doi/full/10.1002/cti2.1274

[4]Basar R,et al.Next-generation cell therapies: the emerging role of CAR-NK cells[J]. Hematology 2014, the American Society of Hematology Education Program Book, 2020, 2020(1): 570-578.

https://ashpublications.org/hematology/article/2020/1/570/474363/Next-generation-cell-therapies-the-emerging-role

[5]Daher M,et al.Outlook for new CAR-based therapies with a focus on CAR NK cells: what lies beyond CAR-engineered T cells in the race against cancer. Cancer Discov 2021; 11: 45–58. doi: 10.1158/2159-8290[J]. Annu Rev Immunol, 1997, 15: 481-504.

https://aacrjournals.org/cancerdiscovery/article/11/1/45/2895/Outlook-for-New-CAR-Based-Therapies-with-a-Focus

[6] Wang Jingwei et al. Research progress on CAR-NK cells [J]. Inner Mongolia Medical Journal, 2022, 54(12): 1508-1510.DOI: 10.16096/J.cnki.nmgyxzz.2022.54.12.029.

[7] Yan Ji et al. Research progress of CAR-NK in the treatment of solid tumors [J]. Modern Oncology, 2023, 31(05): 964-968.

[8]https://www.onclive.com/view/nkx019-showcases-manageable-safety-early-activity-in-r-r-b-cell-non-hodgkin-lymphoma

[9]http://www.phirda.com/artilce_32870.html?cId=1

(source:internetGYSrCYpMJTxsF9XO4CaPfw, reference only)

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