RE: Early Efficacy.4 Jul 2025 10:41
Stu, I am taking YOU up on your advice and doing my own research, so please answer MY question, WHAT IS HG-CT-1 worth??
Yes, there are indeed scenarios in relapsed/refractory Acute Myeloid Leukemia (R/R AML) where a patient might have received an earlier CAR-T cell therapy targeting a different antigen, achieved an initial response (early efficacy), but then relapsed, and could potentially benefit from a FLT3-targeted CAR-T cell therapy.
Here's why and the context:
1. Early Efficacy with CAR-T Against Other Targets in AML:
CAR-T cell therapy for AML is still in earlier stages of development compared to B-cell malignancies (like ALL or lymphoma, where CD19 CAR-T is approved). However, there are numerous ongoing preclinical and early-phase clinical trials targeting various AML-associated antigens.
Common targets that have shown some early efficacy include:
CD33: This is one of the most widely investigated targets for AML CAR-T. Preclinical studies and early clinical trials have shown promise, demonstrating anti-leukemic activity.
CD123: Another prevalent AML antigen that has been explored for CAR-T therapy, with some early positive results.
CLL-1 (C-type lectin-like molecule-1): Also shows expression on AML blasts and has been a target of interest.
Other emerging targets: GPRC5D, FCRL5, etc.
2. Relapse Mechanisms in CAR-T Therapy (General and AML-Specific):
Relapse after CAR-T cell therapy is a known challenge across various malignancies, and several mechanisms contribute to it:
Antigen Escape/Loss: This is a major one. The tumor cells lose or downregulate the targeted antigen, making them "invisible" to the CAR-T cells. This is particularly relevant in heterogeneous diseases like AML. For example, if a CD33 CAR-T was used, the relapsed AML might have lost CD33 expression.
3. Why a FLT3-Targeted CAR-T Could Benefit These Patients:
Antigen Heterogeneity and Escape: AML is highly heterogeneous, meaning different leukemic cells within a patient can express different antigens or varying levels of a single antigen. If a patient relapses after a CD33 CAR-T due to CD33 antigen loss, but their leukemic cells retain or upregulate FLT3 expression, then a FLT3-targeted CAR-T offers a new avenue.
FLT3 is expressed on a high percentage of AML blasts (over 90% in many cases), regardless of FLT3 mutation status. This broad expression makes it an attractive CAR-T target.
Roughly 30% of AML patients have activating FLT3 mutations (FLT3-ITD or FLT3-TKD), which are associated with aggressive disease and poor prognosis, and where FLT3 is particularly highly expressed.
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