April 23, 2024

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How Does Gene Mutation Boost T-cell Anti-Cancer Power?

How Does Gene Mutation Boost T-cell Anti-Cancer Power?



How Does Gene Mutation Boost T-cell Anti-Cancer Power?

Scientists have confirmed for the first time that gene mutations that make T-cell lymphoma stronger can increase the anti-cancer power of T-cells a hundredfold.

In order to survive or spread, cancer cells have become masters of mimicry or disguise.

They can not only mimic the expression of immune checkpoints in normal cells, inhibiting attacks by various immune cells, but also disguise themselves as healthier cells than normal cells, accelerating the elimination of surrounding normal cells. They can even disguise themselves as immune cells, moving freely without hindrance.

Recently, a research team led by Jaehyuk Choi of Northwestern University in the United States and Kole T. Roybal of the University of California, San Francisco, published a groundbreaking research result in the top journal Nature, which enabled immune cells to successfully “learn from” and subdue cancer cells.

How Does Gene Mutation Boost T-cell Anti-Cancer Power?

They conducted a large-scale study on potential driver gene mutations in T-cell lymphoma and found that a fusion mutation of a pair of genes can actually increase the ability of T-cells to fight solid tumors a hundredfold, without any signs of toxicity. In simple terms, they discovered the superpower of T-cell lymphoma. After transplanting it into normal T-cells, normal T-cells gained super anti-cancer abilities.

Although T-cell immunotherapy has fundamentally changed the treatment paradigm for blood cancers, its performance in solid tumors, which account for 90% of adult cancers, has been unsatisfactory. It wasn’t until last month that the FDA approved the first T-cell therapy, lifileucel, for treating solid tumors.

Compared with blood cancers, the difficulty in overcoming solid tumors is mainly due to various factors such as poor persistence of T-cells in the body, strong immune suppression in the tumor microenvironment of solid tumors, and T-cell exhaustion. In simple terms, to make T-cells deal with solid tumors, their strength needs to be further enhanced.

Choi and Roybal’s team noticed that the method to enhance the anti-cancer effect of T-cells in preclinical studies (inactivating PDCD1, TET2, or DNMT3A) is actually a mutation found in T-cell lymphoma. If that’s the case, can gene mutations that solve the above problems be found in T-cell lymphoma?

To answer this question, Choi and Roybal’s team selected 71 potential driver gene mutations in T-cell lymphoma, including 61 point mutations distributed in 40 different genes and 10 gene fusion mutations. They then studied the effects of different gene mutations on T-cell function in a special reporter cell line.

After multiple screenings, CARD11 and PIK3R3 fusion emerged as the winners.

Compared with other mutations, the CARD11-PIK3R3 fusion can significantly enhance the NF-κB and AP-1 signals, as well as the production of IL-2, without increasing NFAT or PD1.

Previous studies have shown that enhancing NF-κB and AP-1 signals rather than NFAT signals helps to combat T-cell dysfunction; and CD8-positive T-cell subpopulations that produce high levels of IL-2 can better maintain a memory phenotype and effector function.

Obviously, the CARD11-PIK3R3 fusion found in CD4-positive skin T-cell lymphoma patients is worth further study.

Subsequently, Choi and Roybal’s team tested the effect of the CARD11-PIK3R3 fusion on the anti-cancer activity of CAR T-cells in two different CAR T-cell models.

They found that whether IL-2 was supplemented or not would affect the anti-cancer effect of normal CAR T-cells, but not the anti-cancer effect of CARD11-PIK3R3 fusion CAR T-cells (which would clear almost all cancer cells regardless of whether IL-2 was used). It’s worth noting that the world’s first approved solid tumor T-cell therapy last month requires the simultaneous use of IL-2.

At a higher dose of 7×106 CAR T-cells, Choi and Roybal’s team found that the control group’s normal CAR T-cells could only control 43% of the tumors, while the tumor control rate of CARD11-PIK3R3 fusion CAR T-cells was 100%.

It is worth noting that CARD11-PIK3R3 fusion T-cells without CD19-CAR have no anti-tumor effect, indicating that the enhanced anti-tumor activity of CARD11-PIK3R3 fusion requires antigen stimulation. This also means that CARD11-PIK3R3 fusion CAR T-cells do not have the risk of autonomous proliferation.

Furthermore, even at high doses, CARD11-PIK3R3 fusion T-cells showed good safety. There were no signs of lymphoma even on day 418 after reinfusion.

Although the above studies were conducted in mouse models of blood tumors, subsequent studies in mouse models of mesothelioma, melanoma, and gastric cancer have all found that CARD11-PIK3R3 fusion can enhance the anti-tumor effect of T-cells (CAR T-cells or TCR T-cells).

In the study of melanoma, Choi and Roybal’s team were surprised to find that even though the number of CARD11-PIK3R3 fusion CAR T-cells was only one percent of normal CAR T-cells, they could control the tumors, while normal CAR T-cells could not. This means that the anti-tumor activity of CARD11-PIK3R3 fusion CAR T-cells has increased by over 100 times.

It is especially worth mentioning that Choi and Roybal’s team also found that CARD11-PIK3R3 fusion CAR T-cell therapy does not even need bone marrow ablation to exert a good anti-solid tumor effect.

Bone marrow ablation has been shown to significantly improve the transplantation and efficacy of CAR T-cells, as well as to carry the risk of mutagenesis and increase the risk of secondary malignant tumors; whereas CARD11-PIK3R3 fusion CAR T-cells do not require this step. This not only indicates that its efficacy is indeed stronger, but also avoids adverse events.

In conclusion, Choi and Roybal’s team’s strategy of “learning from the barbarians to subdue the barbarians” has enabled T-cells to gain a hundredfold power, giving them powerful anti-solid tumor abilities, and further reducing the risk of CAR T-cell therapy.

It is reported that Choi and Roybal’s team have established a new company, Moonlight Bio, and are transforming this new discovery into a new cancer therapy.

How Does Gene Mutation Boost T-cell Anti-Cancer Power?


references:

[1].Garcia J, Daniels J, Lee Y, et al. Naturally occurring T cell mutations enhance engineered T cell therapies. Nature. 2024;626(7999):626-634. doi:10.1038/s41586-024-07018- 7

[2].https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lifileucel-unresectable-or-metastatic-melanoma

(source:internet, reference only)

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