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Drug: CAR-T therapy

Magazine: Nature

Highlights: A clever design that increases the anti-cancer ability of CAR-T therapy

 

More and more cancer patients are being treated with CAR-T cell therapy.

 

CAR, the English full name of Chimeric Antigen Receptor, chimeric antigen receptor, is a kind of “navigation” that can specifically recognize cancer cells, and T is a T cell that plays a role in killing cancer cells.

 

Briefly, CAR-T therapy refers to the isolation of T cells from patients, and then in vitro T cells are engineered to express CARs that recognize cancer cells, and then these CAR-T cells are expanded. Finally, it is returned to the patient to exert anti-cancer effect.

Lymphocytes are attacking cancer cells

 

At present, CAR-T therapy has achieved remarkable results in the treatment of hematological tumors. Two CAR-T therapies have been approved worldwide, namely Novartis Kymriah and Kite Pharma’s Yescarta, for the treatment of acute lymphoblastic leukemia and certain types of non-Hodgkin’s lymphoma.

However, in the treatment of solid tumors, the performance of CAR-T therapy is not satisfactory. This is partly because when a CAR-T cell enters a solid tumor, it may stop killing the tumor cell because of a phenomenon called T cell depletion.

 

On February 27, in a recent study published in the journal Nature, scientists from the La Jolla Institute of Immunology in the United States found a new way to combat T cell depletion, which greatly improved the efficacy of CAR-T therapy.

 

Their research suggests that a family of proteins called Nr4a transcription factors play an important role in regulating genes involved in T cell depletion. Animal experiments have shown that treatment with CAR-T cells that do not express the Nr4a transcription factor results in smaller tumors and longer survival.

Professor Anjana Rao

 

Specifically, in order to investigate the function of CAR-T cells in solid tumors, Professor Anjana Rao of the La Jolla Institute of Immunology and others treated hCD19-positive tumor-bearing mice with CAR-T cells. Analysis showed that “CD8+CAR+ tumor infiltrating lymphocytes” and “CD8+ endogenous tumor infiltrating lymphocytes” expressing the immunosuppressive receptors PD-1 and TIM3 exhibited similar gene expression characteristics and chromatin accessibility. This is related to the secondary activation of the nuclear receptor transcription factors NR4A1 (NUR77), NR4A2 (NURR1) and NR4A3 (NOR1).

 

Further studies have shown that CD8+ T cells from cancer or chronic viral infection patients express high levels of NR4A transcription factors. CAR-T cells lacking all three NR4A transcription factors (Nr4a triple knockout) promote tumor regression and prolong survival of tumor-bearing mice.

 

Most mice treated with “deleted Nr4a-depleted CAR-T cells” survived and their tumors resolved and remained in a small volume during the 90-day experiment. In contrast, almost all mice treated with “Nr4a normally expressing CAR-T cells” died of tumor on day 35 of the experiment.

CAR-T cells lacking the Nr4a transcription factor can reverse tumors and prolong the survival of mice.

Researchers believe that it is a very encouraging finding that transcription factors play an important role in T cell depletion. Despite the long distance between their research and the clinic, these findings enrich the knowledge base for improving cancer immunotherapy and are expected to help solve the dilemma of poor efficacy of CAR-T therapy for solid tumors. Inhibition of NR4A is a promising strategy for cancer immunotherapy. In the future, they will continue to study the role of other transcription factors in T cell depletion, especially those directly affected by NFAT and Nr4a.

Initial CD8+ T cells respond to different trends of acute and chronic infections

At present, there are many other scientists in the world who are conducting research around T cell depletion. This T cell dysfunction caused by chronic antigen stimulation occurs in many chronic infections and cancers, manifested by low or lost effector function and up-regulation of immunosuppressive receptor expression. Depleted T cells can block the immune system’s optimal control of infections and tumors, and immune checkpoint blockade-mediated regeneration of depleted T cells has become an effective treatment for a variety of cancers.

Inhibitory receptor molecular pathway associated with T cell depletion

 

However, most cancer patients initially respond well to immune checkpoint blocking therapies (such as PD-1/PD-L1 antibodies), but this response is not long-lasting. Why is this?

Cover of the paper: The background is functional T cells (green), and the foreground is depleted T cells (gray)

 

Dr. E John Wherry of the University of Pennsylvania School of Medicine answered this question in two Science papers published in 2016.

Blocking the interaction of PD-1/PD-L1 has little effect on the epigenetic characteristics of depleted T cells.

 

The study found that the epigenetic features of depleted T cells are significantly different from those of effector T cells and memory T cells (the latter two cells can produce an effective immune response to viruses and tumors, especially memory T cells, which will have a lasting effect. ). Blocking PD-1 only slightly changes the epigenetic characteristics of depleted T cells.

 

Scientists believe that the irreversibility of depleting the epigenetic fate of T cells limits the efficacy of PD-1/PD-L1 checkpoint inhibitors.

 

Based on this finding, Dr. Wherry et al. suggested that depleted T cells could be reprogrammed at epigenetic levels into functionally persistent functional memory T cells by combining epigenetic drugs with immunological checkpoint inhibitors.

This idea was validated in a Cell paper published in 2017. A team led by Dr. Ben Youngblood of the St. Jude Children’s Research Hospital in the United States confirmed that decitabine, a chemotherapy drug that inhibits DNA methylation, can reverse epigenetic-associated T cell depletion.

 

When the researchers treated the tumor mice with decitabine, the T cells showed enhanced activity, reversing the depleted state; then the mice were treated with PD-1 inhibitors, and the T cells of the mice proliferated actively and had new life. The vitality of T cells. This enhanced T cell proliferation is associated with significant control of tumor growth.

Dr. Youngblood et al believe that these results demonstrate that combined epigenetic reprogramming and immunological checkpoint blockade are expected to improve the efficacy of anti-cancer immunotherapy.

Combined with the newly published Nature paper, it can be found that whether it is CAR-T therapy or immunological checkpoint inhibitors, combined with other methods to better mobilize or change depleted T cells is an important direction to improve efficacy and expand the applicable population.

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