The global efforts to improve CAR T-cell therapy
Within the global efforts to improve CAR T-cell therapy, presentations revolved around engineering of CAR-T, including next-generation CAR T-cells to overcome resistance, improved CAR-T approaches to lymphoid malignancies, targeted genomic insertion, virus-free gene transfer and genome editing, and adaptor/uni-CARs). Current CAR-T trial activities in China were also reviewed.
Click on the titles below to read more and view the presentations (if available).
Keynote lecture: Improved CAR T-cell approaches for lymphoid malignancies (Martin Pule, UK)
Several clinical trials address unmet needs in the use of CAR-T for lymphoid malignancies: An anti-CD19 CAR T-cell (AUTO1) for relapsed/refractory B-ALL tumors, and a CD19/CD22 bispecific CAR T-cell (AUTO3) for relapsed/refractory DLBCL show encouraging results. Trials ought to address the need for cost effective and efficient manufacturing processes, as well as alternative way of improving CAR-T treatments like the optimization of CAR-T through inhibition of immunosuppression in the tumor microenvironment, either through augmentation of CAR T-cells with immune checkpoint inhibitor modules or removal of phosphatase domains .
In T-cell lymphomas, the tumor can be T-cell receptor beta constant 1 (TRBC1), or TRBC2 positive. This is an example where engineering of CAR-T that specifically target one or the other antigen can make a significant clinical difference in a challenging area.
View the presentation here
Keynote Lecture: Updates in CAR T-cell therapy (Carl June, USA)
Looking past CAR-T in ALL, CLL, DLBCL and myeloma, the NY-ESO-1 CRISPR (TCR-PD1) Triple Edited T cell Study (NYCE) – evaluates the feasibility of multiplex human genome editing with CRISPR-Cas9: ddPRC in patients with MM, melanoma, synovial sarcoma or myxoid/round cell liposarcoma. A single infusion of CRISPR/Cas9 triple edited TCR T cells proved safe in 3 patients with no CRS or severe adverse events observed, a stable disease and persistent engraftment of the edited T cells for at least 6 months, suggesting that immunogenicity of Cas9 does not occur. Future work will assess the impact of T cells on NY-ESO1 and LAGE1 expression, and seek to determine haplo-insufficient and biallelic modified cells at a single cell level.
Another promising avenue for research include Fibroblast Activated Protein (FAP) CAR-T in cancer and cardiac fibrosis.
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ROR1 CAR T-cell therapy in CLL and solid tumors (Jennifer Specht, USA)
ROR1 is an orphan tyrosine kinase receptor uniformly expressed on the cell surface of CLL and MCL, as well as a subset of ALL and epithelial cancers such as breast carcinoma. At the Fred Hutchinson Cancer Research Center, in a phase 1 trial, ROR1 CART cells were safely transferred and expanded in vivo, with some evidence of trafficking to solid tumor sites but anti-CAR immune responses were frequently observed in patients with solid tumors and CAR T-cells from expanders transitioned into exhaustion, which was not the case for CAR T-cells from patients with CLL. A first-in-human Phase 1 study (NCT04020575) of huMNC-CAR44 CAR T-cells for advanced MUC1+ breast cancer is also ongoing.
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Liso-cel pivotal TRANSCEND data (Jeremy Abramson, USA)
TRANSCEND NHL001 supports the use of lisocabtagene maraleucel (liso-cel) in the outpatient setting: The largest clinical study reported to date of CD19-directed CAR T-cells in patients with relapsed/refractory aggressive LBCL, (liso-cel) resulted in a rapid, high rate of durable clinical response (53%) across patients subgroups (including uncommon LBCL histological subtypes and those with poor prognostic features), with 12-month overall survival rates exceeding 85% in complete responders.
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Visualizing CAR T-cells at work (Johannes Huppa, Austria)
Molecular imaging approaches can visualize how CAR T-cells recognize antigens, shedding important light on the underlying mode of action: Lck-mediated phosphorylation of the CAR itself and ZAP70 in response to ligand engagement is substandard, hence current CAR formats may open a niche for cancer relapses due to secondary inefficient signaling.
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Keynote Lecture: Current CAR-T trial activities in China (Jianxiang Wang, China)
200 studies, predominately investigator-initiated, are currently happening in China. Major targets include CD19, CD22 and BCMA, and trials are underway across several therapeutic areas including ALL, NHL, AML and MM. Particularly promising outcomes have been achieved to date with use of CAR T-cells in B-ALL and MM. Clinical issues addressed include better outcomes with CD19-targeted CAR T-cells, acceleration of the manufacturing process (e.g., overnight production with the FasT CAR technique) and use of CAR T-cells to treat testicular cancer relapses. No CAR T-cell therapy has yet gained approval in China, although 14 registration trials are ongoing and products are expected on the market within 1 to 2 years.