News > Early data show CAR-NK cells’ potential to overcome CAR-T toxicity – and Takeda is interested

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Early data show CAR-NK cells’ potential to overcome CAR-T toxicity – and Takeda is interested

While CAR-T cells have been able to produce strong clinical responses in many patients with certain blood cancers, they also come with potentially serious hurdles in terms of toxicity, manufacturing and logistics. But some very early data from one of the nation’s largest cancer hospitals may point to an alternative cell therapy approach, and a major drugmaker plans to take it global.

The University of Texas MD Anderson Cancer Center announced Wednesday early results from its Phase I/IIa trial of a CAR-NK cell therapy, which uses natural killer (NK) cells from donors instead of T cells and targets the cell-surface antigen CD19. Data from 11 patients with non-Hodgkin’s lymphoma and chronic lymphocytic leukemia showed eight responding to the therapy, including seven complete responses. After a median of 13.8 months’ follow-up, patients continued to show no evidence of disease, and five received post-remission therapy.

Importantly, none of the patients experienced the toxicities associated with CAR-Ts, such as neurotoxicity and cytokine release syndrome (CRS). Moreover, while allogeneic cell therapies that use donor cells have long attracted concerns about graft-versus-host disease (GvHD), that didn’t occur either. Most toxicity that did occur was from chemotherapy agents used for conditioning patients prior to infusion with the CAR-NK cells.

“I was amazed to see that,” lead investigator Dr. Katy Rezvani, a professor of stem cell transplantation and cell therapy, said in a phone interview. “I wasn’t sure what to expect.”

One of the reasons for the CAR-NK’s favorable toxicity profile may boil down to the types of cells used, Rezvani said. Whereas T cells are genetically matched to individuals, NK cells are not. As such, one person’s NK cells can be injected into another person – or even into a mouse – without the risk of GvHD. That also means allogeneic CAR-NKs don’t need to undergo the complex gene-editing process that allogeneic CAR-Ts do.

Allogene Therapeutics and its partner, Servier, along with Adaptimmune and others are companies developing allogeneic CAR-T therapies. Meanwhile, the two approved CAR-Ts are autologous therapies that use patients’ own T cells, namely Novartis’ Kymriah (tisagenlecleucel) and Gilead Sciences’ Yescarta (axicabtagene ciloleucel).

Although basic biology explains the lack of GvHD in the CAR-NK study, Rezvani said that why the cells didn’t cause CRS or neurotoxicity is not so clear. One reason could be that while T cells and NK cells are similar in many respects, they also produce different kinds of inflammatory cytokines. One of the biomarkers associated with CRS in CAR-T therapy is a peak in the cytokine interleukin-6 (IL-6), which she said was not seen with the CAR-NK cells. currently lists the Phase I/IIa study as having a target enrollment of 36 patients, but Rezvani said the plan now is to increase that enrollment to 60, with further plans for an international, multi-center Phase II study. Several other studies of CAR-NK cells are also listed, many sponsored by biotech companies and academic institutions in China.

For that effort, Tokyo-based drugmaker Takeda Pharmaceutical has in-licensed the CAR-NK, giving it the development name TAK-007, along with programs for CAR-NK’s targeting the antigen BCMA in multiple myeloma, as well as the option of developing two other therapies. While declining to go into detail about which antigens would be targeted, Rezvani said the two other lead CAR-NK programs are in breast cancer and the brain cancer glioblastoma.

The hope is to initiate the multicenter Phase II study in one or two years, depending on various regulatory steps, and work on a trial protocol is already underway, Rezvani said.

A Takeda spokesperson confirmed via email that the company plans to advance the pivotal study of TAK-007 in 2021 and to have four additional oncology cell therapies in the clinic by the end of fiscal year 2020.



12:19 - 12/02/2020    /    Number : 49333    /    Show Count : 173