Are CAR Tregs a reason for CAR therapy failure?


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On 12th of September 2022, Zinaida Good, a postdoctoral fellow at Stanford University, tweeted: “We found a CAR Treg subset in CD19-CAR T cells for lymphoma. We hope that this finding will put us on a path from 40% cure to 100% cure”.
Only five years earlier, FDA had made historical approval for the first chimeric antigen receptor (CAR) T cell therapy. Today, several CAR T cell therapies are available in clinical practice for blood cancer treatment. Although CAR T cells have been showing promising results, more than half of the patients experience disease progression and neurotoxicity. Therefore, the quest to improve the efficacy of the therapy is still ongoing.
How does CAR T cell therapy work? Ideally, our T cells can protect us from cancer. They have T cell receptors on their surface, which allow them to find and destroy tumor cells. However, tumors develop immune evasion mechanisms, and that makes the task difficult for T cells. And that is where the application of CAR T cell therapy comes into play. First, we isolate the patient’s T cells. Next, we modify isolated T cells with the CAR gene. These T cells are activated and multiplied in vitro, and after a few weeks, can be injected back into the patients. CAR helps T cells to seek antigens associated with cancer cells (for instance, CD19 protein of the B cells in certain kinds of blood cancer) and effectively destroy them.
Although CAR T therapy has revolutionized the treatment of blood cancer, there are still high rates of non-responders. So far, several reasons why CAR T therapy fails have been proposed: 1. It could be related to the tumor, for instance, the tumor’s resistance to apoptosis or when the tumor hide or lose antigens that could be recognized by immune cells, 2. Another reason is related to the patient’s characteristics, such as genetic heterogeneity, 3. The last one is related to CAR T cell manufacturing, which until now has been overlooked. This question came to the focus of two independent groups from Standford and Harvard who published their results in Nature Medicine.
Since the patient’s T cells are activated in vitro, adding CAR yields both cytotoxic and helper T cell populations in the final product. Therefore Zinaida Good and colleagues were interested to look at the repertoire of CAR T cells in patient blood on day 7 after infusion. They studied 32 patients with large B cell lymphoma (LBCL). All patients were treated with axicabtagene ciloleucel (axi-cel), a commercially available CAR T cell therapy that targets CD19 receptors on cancerous B cells and eliminates them. They found that a small subpopulation of CAR T cells, consisting of regulatory T cells (Tregs), were significantly higher among non-responders and were also associated with less severe neurotoxicity.
Another study led by Haradhvala analyzed effects of CAR T cell products axi-cel and tisagenlecleucel (tisa-cel) before and after administration to patients with LBCL. They detected elevations in CAR Tregs among nonresponders to axi-cel. Furthermore, they showed what amount of CAR Tregs can lead to relapse in vivo. For this, they engrafted mice with lymphoma cells followed by injection of different cocktails of CAR T cells. The first mix was composed of 95% conventional CAR T cells + 5% CAR Treg cells, and the control group had 95% conventional CAR T cells + 5% of normal T cells. Both groups of mice showed early tumor clearance, but mice receiving CAR Treg cells developed relapse later. Whereas no relapses were observed in the control group. Also, Haradhvala and colleagues assessed the expansion of conventional CAR T cells in the mice two weeks after the treatment. They concluded that as low as 5% CAR Tregs out of total CAR T cells are sufficient for the suppression of conventional CAR T cell expansion in mice, hence, driving tumor recurrence and disease progression at a later stage.

Findings from both groups indicate that CAR Tregs should be extracted from the final product before the infusion to the patients. Will that really solve the problem? Like Good and colleagues, Hardavala’s group also established that a high number of CAR Tregs is associated with less neurotoxicity. We know that under physiological conditions Tregs suppress the effector function of other T cells, preventing excessive immune response and autoimmunity. CAR Tregs likely behave similarly by suppressing other CAR T cells. Interestingly, patients, who received another CAR T product tisa-cel, had almost no CAR Treg cells. However, from a big-picture perspective, tisa-cel is less effective than axi-cell. So, might we succeed by rather adjusting the number of CAR Tregs than getting rid of them? Or will it be beneficial to separate the CAR Tregs during initial treatment, but introduce them later?
Although there are still a lot of questions to answer, both groups have hugely contributed to the improvement of CAR T cell therapy. Identification of CAR Tregs as a biomarker of response and toxicity following CAR T therapy opens a broad space for the prediction of therapy outcomes and optimization of CAR T therapy designs.

Sources:

Good, Z., Spiegel, J.Y., Sahaf, B. et al. Post-infusion CAR TReg cells identify patients resistant to CD19-CAR therapy. Nat Med 28, 1860–1871 (2022). https://doi.org/10.1038/s41591-022-01960-7

Haradhvala, N.J., Leick, M.B., Maurer, K. et al. Distinct cellular dynamics associated with response to CAR-T therapy for refractory B cell lymphoma. Nat Med 28, 1848–1859 (2022). https://doi.org/10.1038/s41591-022-01959-0

Article author: Taras Baranovskyi. Taras is a medical doctor at Immunotherapy Clinic in Kyiv, Ukraine. His research is focused on developing new approaches for overcoming the antimicrobial resistance of Klebsiella pneumoniae. Also, Taras is a part of a team which spreads knowledge of immunology through the ‘Cup of Immunology’ project.

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