Can CAR T cell therapy shortcomings be avoided by NK Cell therapy?

Can CAR T cell therapy shortcomings be avoided by NK Cell therapy

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NK Cell therapy vs CAR T-Cell therapy

The FDA’s approval of the first CAR T cell therapy in 2017 was widely celebrated as a significant advancement in cancer treatment. The method enabled a focused assault on cancer cells by utilizing a patient’s own immune cells, in contrast to the indiscriminate attack carried out by conventional treatments like chemotherapy and radiation.

Although six CAR-Ts have been approved so far, this treatment method is only effective for a certain group of patients and has mostly demonstrated potential in treating blood cancers. However, it is important to note that it also has significant adverse effects. In order to address these limitations, numerous researchers and biotechnology firms have shifted their focus towards natural killer (NK) cells, which constitute a component of the innate immune response—the body’s initial defense mechanism against any form of infection.

Alicja Copik, an associate professor of medicine and core scientist at the University of Central Florida, stated that NK cells have historically been challenging to culture, resulting in them being disregarded.

“The increased knowledge on cultivating NK cells in the laboratory has sparked significant research enthusiasm for these cells,” she said BioSpace. Only one business was studying NK cells ten years ago. Currently, multiple research teams are investigating various applications of cell treatments.


Addressing the obstacles of CAR-T therapy

CAR-T cell therapies entail the modification of T cells, usually obtained from the patient, by genetic engineering. After being separated, these cells undergo genetic modification to enable the expression of chimeric antigen receptors (CARs) on their surface, equipping them with the ability to more effectively identify and combat cancer cells.

Despite this, CAR-Ts have been shown to cause a lot of bad effects, including cytokine release syndrome, neurotoxicity, and hematological problems like anemia and thrombocytopenia. When using allogeneic CAR-Ts, which include using T cells from a donor, there is a potential risk of graft-versus-host disease. This condition occurs when the immune system strongly reacts and rejects the transplanted cells.

“T cells equipped with chimeric antigen receptors (CARs) have the potential to undergo uncontrolled proliferation, resulting in significant adverse effects,” stated Sumiti Jain, the Chief Scientific Officer of ImmuneBridge. ImmuneBridge, a biotechnology business located in San Francisco, secured $12 million in seed funding in 2023 to further the development of natural killer (NK) cells derived from umbilical cord sources. According to Jain, NK cell–based therapies do not induce cytokine release syndrome and neurotoxicity due to their less vigorous growth.

CAR-T therapies have also been linked to the development of secondary malignancies, including leukemias, skin cancers, and T-cell non-Hodgkin lymphomas. In light of this possible adverse reaction, the FDA has recently declared that it will mandate a revision to the boxed warnings of CAR T-cell therapies. This update will notify patients and prescribers about an increased susceptibility to secondary T-cell malignancies.

David Shook, the chief medical officer of Nkarta, a company working on the development of allogeneic CAR-NK cells, told BioSpace that CAR T cell therapies have been mostly unavailable to patients, even though they are helpful. This is partly because they are hard to make. It takes more than two weeks to isolate and manipulate a patient’s T cells before they can be reintroduced into the patient.

“Some patients who meet the criteria for CAR-Ts and are on the waiting list are unable to receive them due to limitations in the manufacturing process,” Shook explained.


Benefits of NK Cell Therapy

Ann Cheung, the chief scientific officer and head of R&D at Dragonfly Therapeutics, a company focused on developing antibodies that stimulate natural killer (NK) cells, pointed out that unlike CAR-T therapies, NK cell therapies do not necessitate lymphodepletion chemotherapy using toxic agents like fludarabine and cyclophosphamide.

“Due to other immune conditions or susceptibility to infections, not all patients are eligible for these chemotherapies,” she said BioSpace. From that perspective, the safety characteristics of NK cell therapies are significantly superior.” In addition, she stated that NK cells function by identifying several antigens, which positions them as formidable candidates for eliminating cancer cells.

Jain says that NK cell treatments have shown promise in treating solid cancers, while CAR-Ts have mostly failed to bring about benefits in this area. CAR-Ts show remarkable efficacy in treating blood cancers, but their effectiveness appears to be significantly diminished when applied to solid tumors,” he says. According to her explanation, NK cells possess superior migratory capabilities into solid tumors compared to CAR-T cells.

These attributes have motivated numerous biotechnology and research organizations to investigate the possibility of utilizing NK cells as therapeutic agents. Nkarta is in the process of creating CAR-NK cells using a collection of NK cells obtained from a donor. Despite the initial success seen with one candidate, NKX101, a mid-term review of Phase I data in 14 patients with acute myeloid leukemia showed a response rate that was much lower than what was seen in the first six patients. As a result, the business decided to downgrade the priority of the program.

Several other businesses are progressing with their development of CAR NK cell treatment prospects. Fate is now conducting Phase I studies for FT522, a potential treatment for B cell lymphoma. Similarly, Century is also in Phase I with its CD19-targeting medication, CNTY-101, for the treatment of B cell malignancies.

While several individuals are directing their attention on genetically manipulating NK cells to augment their capacity to combat cancer, others are utilizing the innate characteristics of NK cells. An instance of this is Artiva Biotherapeutics, a company located in San Diego, which is collaborating with Merck to create a non-genetically modified NK cell therapy that improves the body’s antibody responses to particular types of cancer and autoimmune illnesses. Recently, NKGen Biotech published preliminary results from Phase I of their allogeneic, non-genetically modified NK cell therapy, SNK02.

The data indicates that the treatment was well-tolerated, with all patients successfully completing the eight treatment cycles. Additionally, there were indications of clinical effectiveness against solid tumors that had been previously treated. Jain says that Immune Bridge wants to use the NK cells that can be found in hematopoietic stem cells that are made from umbilical cords because these cells are more likely to be able to fight certain types of cancer.


Future prospects

Despite recent progress, experts indicate that the process of expanding NK cell therapies may not be simple.

“NK cells have a short lifespan,” Shook explained, which means that patients may need a large amount of medication and numerous rounds of injections.

Jain stated that the process of distinguishing NK cells obtained from donors can deplete the cells and diminish their ability to effectively attack cancer cells. “We require long-lasting cell NK therapies,” she stated.

A recent study published in Nature analyzed clinical trial data and found that the therapeutic advantages of NK cell–based therapies typically had a short duration of only a few months before relapse. This is likely attributed to either resistance or low persistence of NK cells. The scientists observed that the typical duration of NK cell persistence varies from a few days to 4 months, with an average of 7 days. They also mentioned that the cryopreservation of NK cells has an additional effect on their ability to proliferate.

Copik is optimistic that some of these therapies will be available for purchase in the future even though the FDA has not yet approved any cancer treatments using NK cells. “Recent studies indicate that NK cell therapies are proving to be effective and demonstrate superior safety profiles when compared to CAR-Ts,” she stated. The best hospitals for CAR T cell therapy in China are conducting clinical trials in this area.

Jain shares a comparable perspective. Patients are engaged in a daily struggle. The availability of a new therapy that is easily obtainable will be a significant breakthrough.

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