A few items re: CAR T therapies and GvHD. Glad our update in GvHD pushed through last week in 6 patients. CAR T can cause GVHD. In my69s report, and a result I found from 3023, it sounds like they have somewhat figured the conflict out. But I have my doubts. Here’s a paper from 2021 concerning CAR T (removing, engineering, returning cells to body) and GvHD (a hyper immune response to foreign proteins planted in the body).
https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.17544
“Conclusions and perspectives
Engineered CAR T cells have improved clinical outcomes in patients with relapsed/refractory haematological malignancies. HCT is an important treatment modality in patients with multiple high-risk haematological malignancies. However, post-HCT relapse remains a major cause of mortality. CAR T cells represent an attractive therapeutic option in this setting. Despite the encouraging results in early clinical trials outlined here (Tables I and II), larger prospective clinical studies are needed to confirm these results and compare CAR T cells to other salvage therapies post-HCT. Additionally, further elucidation of the mechanisms governing the risk of GVHD in the setting of CAR T cell use post-HCT is needed to guide strategies aimed at reducing the risk for GVHD, while maximising the desirable anti-tumour activity. Thus, carefully planned pre-clinical studies in appropriate immune-competent models would be pivotal to move the field forward.
For example, the use of lymphodepleting chemotherapy before CAR T cell administration has been associated with greater CAR T-cell expansion and improved outcomes.51, 70, 71 This is thought to be mediated by multiple effects including promoting a favourable homeostatic milieu for the infused CAR T cells to expand44, 72, 73 and possibly by reducing anti-CAR T-cell immunity.44, 74 However, studies of donor-derived CAR T cells have largely omitted the use lymphodepleting chemotherapy in part because of the hypothetical increased risk and/or severity of GVHD. Future studies should aim to determine whether the use of lymphodepleting chemotherapy is safe in the setting of donor-derived CAR T-cell therapy and whether it improves anti-tumour activity or not.
Moreover, the development of safe, ‘off-the-shelf’ CAR T cells for use in non-HCT patients or as third-party therapeutic agents in patients with prior HCT would dramatically expand the potential applications of these novel therapies. To facilitate that, strategies that can reduce the risk of GVHD would be instrumental and results of ongoing trials using allogeneic CAR VSTs as well as multiply edited CAR T cells lacking the expression of TCRs will be highly informative. Additionally, efforts aimed at developing more effective therapies to prevent and treat GVHD are needed. For example, Shrestha et al.75 developed anti-C83 CAR T cells that effectively prevented/treated GVHD in pre-clinical models and had promising anti-AML activity. Lastly, different groups are also investigating the use of other immune cell types that are less prone to causing GVHD in the allogeneic setting, as platforms for cellular immunotherapy. These include CAR-engineered NK cells,76 invariant NK T cells77 and γδ T cells.78 However, the use of these cells is precluded by other obstacles including manufacturing challenges given that these cells are present are much lower frequencies in donors. Nevertheless, both NK cells79 and NK T cells80 have been successfully tested in recent pivotal clinical trials. Of particular relevance to the present review Liu et al.79 reported on the use of allogeneic cord blood-derived anti-CD19 CAR-NK cells after lymphodepletion in patients with CD19+ non-Hodgkin lymphoma and chronic lymphocytic leukaemia. In this report, seven of 11 patients achieved CR, while no GVHD was reported. Longer follow-up periods and larger studies are needed to confirm these findings, but this report suggests that allogeneic NK cells may represent an important platform for the production of engineered cellular therapies that carry a low risk of GVHD. In another intriguing form of T-cell immunotherapy Lulla et al.81 used true donor-derived T cells reactive against tumour-associated antigens in patients with AML or myelodysplastic syndrome who relapsed after HCT. They reported on outcomes for 25 patients, 17 of which were treated while in remission and eight were treated with active disease. In all, 11 of the former 17 patients did not relapse at the time of the report publication (with median leukaemia-free survival not reached at a median follow up of 1·9 months and an estimated 2-year overall survival of 77%). Two of the eight patients who were treated with active disease refractory to salvage chemotherapy achieved objective responses (one CR and one partial remission). Importantly, three of 25 patients developed acute GVHD (Grade 1 or 2) and four out of 25 patients developed chronic GVHD (Grade 1 or 2).
Overall, the field of cellular immunotherapy in general, and CAR T-cell therapy in particular, is moving in exciting directions and careful consideration of the mechanisms and risks of GVHD will be important to safely expand access to CAR T cells and provide hope to patients who otherwise have limited therapeutic options available.”
——————
Movement in 25 patients in GBM at Penn. Movement in CYDY GvHD data with FDA.
I think CYDY could solve all of CAR T’s challenges with GvHD.
——————-
This part caught my attention.
“This research is funded by Kite, a Gilead Company, (NCT05168423), and grants from the National Institutes of Health (R35NS116843 and R35NS097370).”
https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.17544
“Conclusions and perspectives
Engineered CAR T cells have improved clinical outcomes in patients with relapsed/refractory haematological malignancies. HCT is an important treatment modality in patients with multiple high-risk haematological malignancies. However, post-HCT relapse remains a major cause of mortality. CAR T cells represent an attractive therapeutic option in this setting. Despite the encouraging results in early clinical trials outlined here (Tables I and II), larger prospective clinical studies are needed to confirm these results and compare CAR T cells to other salvage therapies post-HCT. Additionally, further elucidation of the mechanisms governing the risk of GVHD in the setting of CAR T cell use post-HCT is needed to guide strategies aimed at reducing the risk for GVHD, while maximising the desirable anti-tumour activity. Thus, carefully planned pre-clinical studies in appropriate immune-competent models would be pivotal to move the field forward.
For example, the use of lymphodepleting chemotherapy before CAR T cell administration has been associated with greater CAR T-cell expansion and improved outcomes.51, 70, 71 This is thought to be mediated by multiple effects including promoting a favourable homeostatic milieu for the infused CAR T cells to expand44, 72, 73 and possibly by reducing anti-CAR T-cell immunity.44, 74 However, studies of donor-derived CAR T cells have largely omitted the use lymphodepleting chemotherapy in part because of the hypothetical increased risk and/or severity of GVHD. Future studies should aim to determine whether the use of lymphodepleting chemotherapy is safe in the setting of donor-derived CAR T-cell therapy and whether it improves anti-tumour activity or not.
Moreover, the development of safe, ‘off-the-shelf’ CAR T cells for use in non-HCT patients or as third-party therapeutic agents in patients with prior HCT would dramatically expand the potential applications of these novel therapies. To facilitate that, strategies that can reduce the risk of GVHD would be instrumental and results of ongoing trials using allogeneic CAR VSTs as well as multiply edited CAR T cells lacking the expression of TCRs will be highly informative. Additionally, efforts aimed at developing more effective therapies to prevent and treat GVHD are needed. For example, Shrestha et al.75 developed anti-C83 CAR T cells that effectively prevented/treated GVHD in pre-clinical models and had promising anti-AML activity. Lastly, different groups are also investigating the use of other immune cell types that are less prone to causing GVHD in the allogeneic setting, as platforms for cellular immunotherapy. These include CAR-engineered NK cells,76 invariant NK T cells77 and γδ T cells.78 However, the use of these cells is precluded by other obstacles including manufacturing challenges given that these cells are present are much lower frequencies in donors. Nevertheless, both NK cells79 and NK T cells80 have been successfully tested in recent pivotal clinical trials. Of particular relevance to the present review Liu et al.79 reported on the use of allogeneic cord blood-derived anti-CD19 CAR-NK cells after lymphodepletion in patients with CD19+ non-Hodgkin lymphoma and chronic lymphocytic leukaemia. In this report, seven of 11 patients achieved CR, while no GVHD was reported. Longer follow-up periods and larger studies are needed to confirm these findings, but this report suggests that allogeneic NK cells may represent an important platform for the production of engineered cellular therapies that carry a low risk of GVHD. In another intriguing form of T-cell immunotherapy Lulla et al.81 used true donor-derived T cells reactive against tumour-associated antigens in patients with AML or myelodysplastic syndrome who relapsed after HCT. They reported on outcomes for 25 patients, 17 of which were treated while in remission and eight were treated with active disease. In all, 11 of the former 17 patients did not relapse at the time of the report publication (with median leukaemia-free survival not reached at a median follow up of 1·9 months and an estimated 2-year overall survival of 77%). Two of the eight patients who were treated with active disease refractory to salvage chemotherapy achieved objective responses (one CR and one partial remission). Importantly, three of 25 patients developed acute GVHD (Grade 1 or 2) and four out of 25 patients developed chronic GVHD (Grade 1 or 2).
Overall, the field of cellular immunotherapy in general, and CAR T-cell therapy in particular, is moving in exciting directions and careful consideration of the mechanisms and risks of GVHD will be important to safely expand access to CAR T cells and provide hope to patients who otherwise have limited therapeutic options available.”
——————
Movement in 25 patients in GBM at Penn. Movement in CYDY GvHD data with FDA.
I think CYDY could solve all of CAR T’s challenges with GvHD.
——————-
This part caught my attention.
“This research is funded by Kite, a Gilead Company, (NCT05168423), and grants from the National Institutes of Health (R35NS116843 and R35NS097370).”
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