Novel CAR-T cell therapy shows promise against calreticulin mutant neoplasms

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Published: 26 Jun 2024
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Dr Alexandros Rampotas - UCL Cancer Institute, London, United Kingdom

Dr Alexandros Rampotas speaks to ecancer about the development and evaluation of a CAR-T cell therapy targeting mutCALR+ neoplasms.

Mutant calreticulin (CALR) is an attractive immunotherapy target.

This study was conducted to pre-clinically validate a second-generation, 4-1BB chimeric antigen receptor T-cell (CAR-T) therapy designed to target mutant CALR (mutCALR) driven myeloproliferative neoplasms.

As a result of this study, a first-in-class CAR-T cell therapeutic to target mutCALR-driven myeloproliferative blood cancers has been developed.

Dr Rampotas concluded by discussing the significance of this study and its next steps.

Novel CAR-T cell therapy shows promise against calreticulin mutant neoplasms

Dr Alexandros Rampotas - UCL Cancer Institute, London, United Kingdom

We developed, along with Dr Martin Pule and Dr Claire Roddie, a novel CAR T-cell therapy for calreticulin mutated myelofibrosis. Myelofibrosis is a very challenging disease, there aren’t many curative treatments other than an allogeneic stem cell transplant which is only available for a small subgroup of patients. Even in that setting there is up to 25% treatment-related mortality. There have been quite a few treatments that have become available in recent years but none of these treatments are really disease modifying, they’re not curative treatments.

Calreticulin is a fascinating molecule because the mutations in this protein result into a novel C-terminus which we can target specifically with a binder that would only target the expression of mutated calreticulin malignant cells.

Now, also it gets more interesting because in order to cause the disease mutated calreticulin needs to bind to the thrombopoietin receptor, they are expressed together in the surface and that leads to an aberrant activation of the thrombopoietin receptor, firing up the malignant clone. Immunotherapies can target molecules that are expressed on the surface of cells but this molecule is only expressed on the malignant clone, it is not expressed on the normal cells and it is the product of a disease-driving mutation. So the perfect triad for an immunotherapeutic approach.

So, our CAR T-cell therapy has been able to eliminate cancer cell lines that are bearing this target and then we tested it against patient samples. We isolated stem cells from patients with myelofibrosis and our CAR T-cell therapy was able to eliminate the malignant clone among these stem cells without having any off-target toxicity against JAK2 mutated stem cells or other relevant targets.

Our next step was to test our CAR T in an in vivo model. So we used an NSG xenograft model with a quite aggressive cell line that usually induces death in mice within 2-3 weeks. Our CAR T was able to control the proliferation of this cell line and to statistically significantly prolong survival in murine cohorts. We also looked for evidence of tumour in these mice after treatment with CAR T cell and the tumour was almost completely eliminated. Also the CAR T-cells were able to expand in this murine environment and work very well.

So we are very excited about this treatment, we want to take it to the clinic. We think that it could potentially be practice changing. Hopefully we will be able to start a phase I first in human trial where we will be testing this treatment on calreticulin mutated myelofibrosis patients.

Is there anything else you would like to add?

I would like also to thank our collaborators in the University of Oxford, the Bethan Psaila lab and Zoe Wong have done some of this work. Also my supervisors, Dr Claire Roddie and Martin Pule as well as the MRC and the Blood Cancer Research UK who have funded this research that wouldn’t have been otherwise possible.