Editor's note:
With the vigorous development of CAR-T cell therapy , new CAR-T concepts and technologies will appear every month. The editor tries to catalog some of them here to encourage our patients - on the road to fighting cancer, there are countless scientists and medical workers fighting side by side with us and constantly achieving new victories.
1, CAR-T cells targeting GPRC5D
CAR-T cells targeting GPRC5D are second-generation CAR-T cells developed by researchers using human B-cell-derived GPRC5D single-strand variable fragments, 4-1BB costimulatory domains and CD3ζ signaling domains. They are used to treat patients with relapsed or multiple myeloma , including those who have received BCMA-oriented treatment.
The researchers started with the initial dose of 25x106 CAR-T cells and gradually increased to the highest dose of 450×106 CAR-T cells. 71% of patients with responded, especially in patients with limited treatment options or no other treatment options. In terms of
safety, at a 450×106 CAR-cell dose, one patient suffered from grade 4 cytokine release syndrome and immune effector cell-related neurotoxic syndrome, and two patients suffered from grade 3 cerebellar disease of unknown cause. Among the 12 patients receiving the 25x106 to 150×106 cell dose, did not develop cerebellar disease, any level of immune effector cell-associated neurotoxic syndrome, grade 3 or higher cytokine release syndrome.
Researchers finally determined that 150×106 CAR-T cells are the maximum tolerated dose of . At this maximum tolerated dose and lower dose, the percentage of responding patients was 58% and the duration of response was 7.8 months. Patients who were usually excluded from other CAR-T cell therapy studies also responded, including patients with non-secretory myeloma, patients with previous allogeneic hematopoietic stem cell transplants, patients with extramedullary disease, and patients with previous BCMA-oriented treatment.
(PET-CT images of patients receiving 25×106 CAR-cell dose at baseline and after treatment)
2, CAR Treg cell recognition resistant patients
After treatment with CAR-T cells, effective biomarkers need to be found.
Researchers studied CAR-T cells in peripheral blood of 32 LBCL patients treated with CAR-T cells. They found that circulating CD4+CD57–Helios+ CAR-T cells at day 7 after infusion were associated with cancer clinical progression and mild neurotoxicity. These cells are non-clonal, and has a Treg gene expression program and low cytotoxic potential , which is consistent with the classic Treg cells derived from thymus . Its inhibitory function will reduce anti-tumor response, reduce T cell toxicity, and slow down T cell expansion. Verification cohort analysis demonstrated the association between higher CAR Treg cells and clinical progression and milder neurotoxicity.
researchers used a second validation cohort to confirm that the frequency of CAR Treg cells was inversely proportional to total CAR-T cell amplification, but was not related to the tumor burden quantified by lactate dehydrogenase levels. Using a model combining CAR Treg and lactate dehydrogenase levels combined with , it outperforms each feature alone in predicting clinical responses.
This study proves that CAR Treg cell expansion is a novel biomarker of response and toxicity after CAR-T cell therapy, and may be used to regulate human CAR-T lymphocyte response.
(Treg identity of CD4+CD57-Helios+ CAR T cells by single-cell sequencing)
3, a new pathway to regulate the adhesion of CAR-T cells and solid tumor cells
3, a new pathway to regulate the adhesion of CAR-T cells and solid tumor cells
recently published in the journal Nature , a study published in the journal Nature , showed that the IFNγR pathway in solid tumors affects the efficacy of CAR-T cells by affecting the duration and affinity of cell binding.
Researchers established U87 cells that knocked out IFNγR1, JAK1 and JAK2 genes, respectively. The killing tests conducted later showed that these single gene knockouts caused cancer cells to develop drug resistance to CAR-T cells by and . The drug resistance phenomenon was further verified using the U87 cell subcutaneous xenograft model.The researchers tried two other models, and the results consistently showed that cancer cells are opposed to CAR-T cytotoxicity and are not related to CAR, but to the result of single gene knockout.
Researchers tested other solid tumors , such as pancreatic cancer cells, ovarian cancer cells and lung cancer cells. Both in vitro and in vivo results showed that after the IFNγR pathway dysfunction, all solid tumor cells tested were more resistant to the killing of CAR-T cells.
Further studies found that cell adhesion pathway was significantly enriched in U87 cells. If IFNγ-secreting CAR-T cells can be activated, the IFNγR signaling pathway can be triggered, and the expression of ICAM-1 can be upregulated, thereby further strengthening the interaction between ICAM-1 and LFA-1 (as shown in the figure below) and improving the efficacy of CAR-T cells.
Paper summary chart
4, intestinal microbiota regulates CAR-T cell treatment
CAR-T cell treatment has a high success rate in blood cancer, but the patient's individual characteristics may reduce the benefits of treatment.
By comparing the diversity and composition of intestinal microbiology in different CAR-T cell treatment stages in clinical trial ChiCTR1800017404, the researchers found that the treatment response of multiple myeloma, acute lymphocytic leukemia and non-Hodgkin lymphoma , and the occurrence of severe cytokine release syndrome in multiple myeloma was correlated with specific intestinal microbiota changes.
(1) After CAR-T cell treatment, in patients with complete remission, most important bacterial genus in their intestines, such as faecalis, Rochetella and Rumenococci are all enriched with . Compared with patients with partial remission, the abundance of Bifidobacterium , Presbyteriana, Sartres, Spiropox , Prevots, and Collins were higher in patients with advanced remission before and after CAR-T cell treatment.
(2) In non-Hodgkin's lymphoma , faecalis, bifidobacterium and rumenococci are significantly enriched in patients with complete and partial remission and patients without remission. For acute lymphocytic leukemia , the researchers observed that the enrichment of Bifidobacterium, Rocheri and Collins in patients with multiple myeloma and non-Hodgkin's lymphoma was different.
(3) By stratifying patients by bacterial abundance , the researchers observed that the progression-free survival of patients with high Sartella abundance was significantly extended. This association is still significant even after stratification by point-of-time. However, for Faecoli, no correlation was observed.
(4) By analyzing the association between cytokine syndrome grade and bacterial genus taxa , the researchers found that patients with worsening cytokine syndrome had their Bifidobacteria not only increased during the cytokine syndrome window, but also during the early stages. In patients with high cytokine syndrome grade, Candida albicans are significantly enriched during the window period. Among the 38 patients with validated multiple myeloma, no significance of Bifidobacterium or Thoraminobacterium was observed in different cytokine syndrome rating groups.
This study is of great significance to understand the biological role of microbial in CAR-T treatment response in patients with hematologic malignancy and may guide therapeutic interventions to improve efficacy.
(positron emission tomography before and after CAR-T cell treatment and 5 months after treatment-computed tomography showed that a large number of bone metastasis of MM was completely eliminated)
References:
1, Mailankody S, Devlin S M, Landa J, et al. GPRC5D-targeted CAR T cells for myeloma[J]. New England Journal of Medicine, 2022, 387(13): 1196-1206.
2, Good Z, Spiegel J Y, Sahaf B, et al. Post-infusion CAR TReg cells identify patients resistant to CD19-CAR therapy[J]. Nature Medicine, 2022, 28(9): 1860-1871.
3, Hong L, Ye L. The interferon-γ receptor pathway: a new way to regulate CAR T cell-solid tumor cell adhesion[J]. Signal Transduction and Targeted Therapy, 2022, 7(1): 1-2.
4, Hu Y, Li J, Ni F, et al. CAR-T cell therapy-related cytokine release syndrome and therapeutic response is modulated by the gut microbiome in hematologic malignancy[J]. Nature communications, 2022, 13(1): 1-14.
The researchers tried two other models, and the results consistently showed that cancer cells are opposed to CAR-T cytotoxicity and are not related to CAR, but to the result of single gene knockout.Researchers tested other solid tumors , such as pancreatic cancer cells, ovarian cancer cells and lung cancer cells. Both in vitro and in vivo results showed that after the IFNγR pathway dysfunction, all solid tumor cells tested were more resistant to the killing of CAR-T cells.
Further studies found that cell adhesion pathway was significantly enriched in U87 cells. If IFNγ-secreting CAR-T cells can be activated, the IFNγR signaling pathway can be triggered, and the expression of ICAM-1 can be upregulated, thereby further strengthening the interaction between ICAM-1 and LFA-1 (as shown in the figure below) and improving the efficacy of CAR-T cells.
Paper summary chart
4, intestinal microbiota regulates CAR-T cell treatment
CAR-T cell treatment has a high success rate in blood cancer, but the patient's individual characteristics may reduce the benefits of treatment.
By comparing the diversity and composition of intestinal microbiology in different CAR-T cell treatment stages in clinical trial ChiCTR1800017404, the researchers found that the treatment response of multiple myeloma, acute lymphocytic leukemia and non-Hodgkin lymphoma , and the occurrence of severe cytokine release syndrome in multiple myeloma was correlated with specific intestinal microbiota changes.
(1) After CAR-T cell treatment, in patients with complete remission, most important bacterial genus in their intestines, such as faecalis, Rochetella and Rumenococci are all enriched with . Compared with patients with partial remission, the abundance of Bifidobacterium , Presbyteriana, Sartres, Spiropox , Prevots, and Collins were higher in patients with advanced remission before and after CAR-T cell treatment.
(2) In non-Hodgkin's lymphoma , faecalis, bifidobacterium and rumenococci are significantly enriched in patients with complete and partial remission and patients without remission. For acute lymphocytic leukemia , the researchers observed that the enrichment of Bifidobacterium, Rocheri and Collins in patients with multiple myeloma and non-Hodgkin's lymphoma was different.
(3) By stratifying patients by bacterial abundance , the researchers observed that the progression-free survival of patients with high Sartella abundance was significantly extended. This association is still significant even after stratification by point-of-time. However, for Faecoli, no correlation was observed.
(4) By analyzing the association between cytokine syndrome grade and bacterial genus taxa , the researchers found that patients with worsening cytokine syndrome had their Bifidobacteria not only increased during the cytokine syndrome window, but also during the early stages. In patients with high cytokine syndrome grade, Candida albicans are significantly enriched during the window period. Among the 38 patients with validated multiple myeloma, no significance of Bifidobacterium or Thoraminobacterium was observed in different cytokine syndrome rating groups.
This study is of great significance to understand the biological role of microbial in CAR-T treatment response in patients with hematologic malignancy and may guide therapeutic interventions to improve efficacy.
(positron emission tomography before and after CAR-T cell treatment and 5 months after treatment-computed tomography showed that a large number of bone metastasis of MM was completely eliminated)
References:
1, Mailankody S, Devlin S M, Landa J, et al. GPRC5D-targeted CAR T cells for myeloma[J]. New England Journal of Medicine, 2022, 387(13): 1196-1206.
2, Good Z, Spiegel J Y, Sahaf B, et al. Post-infusion CAR TReg cells identify patients resistant to CD19-CAR therapy[J]. Nature Medicine, 2022, 28(9): 1860-1871.
3, Hong L, Ye L. The interferon-γ receptor pathway: a new way to regulate CAR T cell-solid tumor cell adhesion[J]. Signal Transduction and Targeted Therapy, 2022, 7(1): 1-2.
4, Hu Y, Li J, Ni F, et al. CAR-T cell therapy-related cytokine release syndrome and therapeutic response is modulated by the gut microbiome in hematologic malignancy[J]. Nature communications, 2022, 13(1): 1-14.
