MIT team develops vaccine-enhanced CAR-T therapy
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MIT team develops vaccine-enhanced CAR-T therapy, which can fight solid tumors and immune escape cancer cells through antigen diffusion
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MIT team develops vaccine-enhanced CAR-T therapy, which can fight solid tumors and immune escape cancer cells through antigen diffusion
Chimeric antigen receptor T-cell therapy (CAR-T) has achieved gratifying results in blood cancers, but it has always been weak in solid tumors.
One of the reasons is that there are not enough antigens for CAR-T to recognize. On the one hand, the high heterogeneity of tumors makes not all cancer cells express the antigen targeted by CAR, on the other hand, antigen loss will also occur during treatment.
On July 05, the MIT team published a new paper in the journal “Cell”. The researchers developed a vaccine-enhanced CAR-T method to activate CAR-T cell expansion and enhance anti-tumor ability through CAR ligands.
Surprisingly, the researchers found that this can also induce antigen spread (AS), activate the anti-tumor immunity of the original immune system, and greatly enhance the anti-cancer effect.
Thesis title map
The “vaccine” used in the study is formed by coupling the CAR ligand with the amphiphilic polymer lipid tail + adjuvant.
After injection, the ligand can be bound to albumin and transported to the draining lymph node (dLN) and decorated to the giant lymph node. surface of phagocytes and dendritic cells.
These cells then meet with CAR-T, and under the stimulation of co-stimulatory receptor signals and cytokines, the proliferation and anti-tumor immune function of CAR-T are enhanced.
Researchers of this method completed it as early as 2019. At that time, they found that not only the anti-tumor ability of CAR-T cells was enhanced, but also the activity of endogenous T cells that recognized non-CAR-T targets was greatly increased.
Principle of action of vaccine-enhanced CAR-T
To understand the mechanism, the researchers tested the effect of vaccine-enhanced CAR-T, which targets EGFR, in the EGFRvIII + CT-2A glioblastoma mouse model.
After the vaccine and CAR-T injections were completed, mouse splenocytes were isolated on day 21 of the experiment and co-cultured with EGFRvIII – CT-2A cells to detect endogenous T cell responses to non-CAR-T targets.
It can be seen from the figure that the combination of CAR-T+ vaccine did give the aborigines a big boost for some reason, showing a significant endogenous T cell response .
CAR-T+ vaccines activate endogenous T cell responses
Similar results were observed in the same experiment in the B16F10 melanoma mouse model. Apparently, the combination of CAR-T+vaccine induced antigenic spread (AS) .
The researchers also analyzed the phenotype and function changes of endogenous T cells after CAR-T+ vaccine, and found that CD8 and CD4 T cells in tumor infiltrating lymphocytes increased significantly, and the proportion of Treg decreased slightly .
The proportion changes of the five main T cell subsets obtained by transcriptome analysis can be seen in the figure below.
Changes in 5 major T cell subsets
Gene differential expression analysis found that the transcripts of CD8 T cells, cytotoxicity and T cell activation in the CAR-T+ vaccine group were significantly up-regulated, and the expression of IFN-γ, granzyme B, and TNF-α increased. Transcripts associated with Th1 function were elevated in CD4 T cells.
This shows that CART+ vaccine can enhance the anti-tumor ability of tumor-infiltrating CD8 T cells and promote the differentiation of CD4 T cells to Th1 phenotype .
The researchers continued to analyze the impact of AS brought by CAR-T+ vaccine on recurrence.
In RAG1 −/− immunodeficient mice carrying mEGFRvIII + CT-2A, although the CAR-T+ vaccine initially also brought good therapeutic effects, most animals relapsed 20-50 days after treatment .
Analysis of recurrent tumors reveals that loss or downregulation of EGFR expression is the main immune escape mechanism.
Immunodeficient mice are more likely to relapse after treatment than wild-type
Researchers have also tried to use CAR-T+ vaccines to treat heterogeneous tumors.
EGFRvIII + CT-2A and EGFRvIII – CT-2A cells were mixed and transplanted into mice in different proportions.
When 100% of the cells expressed EGFRvIII, the mice could respond to CAR-T + vaccine treatment and showed long-term remission; when EGFRvIII – CT- When the proportion of 2A cells reaches 20%, 50% of mice can still achieve complete remission .
Treatment effect of different proportions of mixed tumors
Further analysis found that IFN-γ produced by CAR-T cells is crucial for the induction of AS.
While IFN-γ promotes the cytotoxic killing of CAR-T cells, it also promotes the recruitment and antigen uptake of dendritic cells, causing them to secrete IL-12, which in turn can enhance the expression of IFN-γ and the expression of T cells in T cells. Cytotoxic activity.
All in all, antigen heterogeneity and antigen loss are the key mechanisms of tumor immune escape and drug resistance in CAR-T therapy.
The vaccine-enhanced CAR-T proposed in this paper proposes a new solution through antigen diffusion, which provides a basis for design New CAR-T clinical trials provide direction.
References:
[1] https://www.cell.com/cell/fulltext/S0092-8674(23)00642-6
MIT team develops vaccine-enhanced CAR-T therapy, which can fight solid tumors and immune escape cancer cells through antigen diffusion
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