Advanced Therapies: Lessons Beyond Approval

Recent studies highlight the cancer risks from cell and gene therapies, but it may not be as clear a picture as hoped

The emergence of cell and gene therapies has enabled us to target diseases that we simply could not get close to using small molecule approaches and has rocketed them into the limelight for drug discovery. The promise of being able to re-engineer cells to be more effective, in the case of genetically modified immune cells, or correcting a genetic mutation, in the case of gene therapies, has opened the door to targeting many life-threatening diseases.

The technology involved with both approaches has demonstrated life changing improvement and, in many cases, lifesaving changes to patients and so will grow in their ability to influence how we develop therapeutics.
As with many groundbreaking technologies, we still have much to learn about the clinical behaviours of these therapies. Over the past year we have seen several papers published that have reviewed rare and unexpected side effects in a small subset of patients that underwent either CAR (Chimeric Antigen Receptor) T cell-based therapies or genetically modified stem cells.

Clarifying these concerns, the FDA issued a letter in November 2023 confirming the risk of T-cell malignancies from all currently approved BCMA-directed and CD19-directed genetically modified autologous CAR T cell immunotherapies.

Initial concerns focused on whether these observations were caused by the genetic alteration made by both therapeutics. Could the methodology of making genetic alterations to these cells somehow make them more likely to cause T-cell cancers and myeloid malignancies? And what are the actual risks of integration of the construct at an oncogenic locus within the genome?

Are CAR-T cell therapies causing T-cell cancers?

In the case of CAR-T therapies, publications by Zhou et al (2024) and Verdun et al (2024) highlight twenty-two cases of T-cell cancers that were reported post treatment out of approximately 34,000 infusions. In three of these cases for which genetic testing was performed, the CAR transgene was detected in the malignant clone, indicating that the CAR-T product was associated with the development of the T-cell cancer. I use the word "associated" with good reason; at this point it is not possible to say whether the CAR transgene was the causative element. While the CAR was found in several of the patients' malignant cells, it should also be pointed out that the malignant clone was present in the apheresis material, suggesting this was a selection event.

In the case of CAR transgenes, we have three plausible possibilities; insertional mutagenesis; bridging therapies and clonal selection through expansion.

• Insertional mutagenesis is when a CAR transgene integrates at an oncogenic locus in the genome.
• Bridging therapies including include immunotherapy, chemotherapy, and radiotherapy are cytotoxic in nature and increase the risk of genetic mutations, usually in the lead up to CAR-T therapy.
• Clonal selection through expansion could occur when these cells are being expanded after genetic modification and prior to being returned to the patient. Under these conditions, any cells that possess a mutation leading to rapid growth will form a greater part of that cell population and may lead to dysregulated cell growth.

At this stage, the FDA guidance is for patients and clinical trial participants who have received CAR-T cell treatments is for life-long monitoring for new malignancies. From a therapeutic development perspective, additional review of the cellular properties following expansion may be required to better understand oncogenic risk.

It is important to understand these risks of therapy induced malignancies in the context of non-relapse mortality (NRM) after CAR therapy, estimated at 6-10% mortality from multiple causes across multiple cancer types, with over half of these NRM causes being infection-related deaths.

Gene therapies and malignancies

In the field of gene therapies, Chapman et al (2023) published their work reviewing the possible cause of myeloid malignancy in patients who have received gene therapy stem cells. In the early days of gene therapy there were reports of vector insertion-related leukaemias in patients that were related to the viral vector used for transgene delivery. Modern vector design has reduced these risks of insertional mutagenesis and yet myelodysplastic syndrome (MDS)), and acute myeloid leukaemia (AML) have been detected in 2 out of 47 patients who had recently undergone gene therapy treatment for sickle cell disease (SCD), potentially indicating that these adverse events are not linked to insertional mutagenesis. Chapman et al put this down to four reasons:

• An elevated mutation rate due to SCD itself
• Mutations resulting from ex vivo manipulation and transplantation of HSCs, including insertional mutagenesis
• Mutations in any surviving residual HSC fraction due to conditioning chemotherapy unrelated to vector insertions
• Positive selective pressure on HSCs containing pre-existing driver mutations

Through their extensive research, they uncovered that some SCD patients have an elevated mutation risk and that selective pressure on hematopoietic stem cells containing pre-existing driver mutations could increase the leukaemia risk in gene therapy trials for SCD.
This research opens the door to a much greater need for genetic assessment of patients to ensure a clear understanding of their suitability and the risks posed by gene therapy treatments in these patient populations.

Taken together, these publications shine a light on the potential risks from our treatment processes as well as the gene therapy and CAR-T therapies themselves in the absence of thorough genetic review of cells prior to their re-introduction into patients. The greater our understanding of such risks, the easier it will be to mitigate them and to reduce the adverse event rate in such essential and groundbreaking therapies.

References:
1. Zhou Z., Zhang G, Xu Y., Yang S., Wang J. & Lu Q. (2024) Cancer Letters 597; 217083
2. Chapman M.S., Cull A.H., Ciuculescu M.F., Esrick E.B., Mitchell E., Jung H., O'Neill L., Roberts K., Fabre M.A., Williams N., Nangalia J., Quinton J., Fox J.M., Pellin D., Makani J., Armant M., Williams D.A., Campbell P.J. & Kent D.G. (2023) Nature Medicine 29; 3175-3183
3. Verdun N. and Marks P. (2024) New England Journal of Medicine 390,7; 584 - 586
4. Cordas dos Santos D.D., Tix T., Shouval R., Gafter-Gvili A., Alberge J-B., Cliff E.R.S., Theurich S., von Bergwelt-Baildon M., Ghobrial I.M., Subklewe M., Perales M-A. & Rejeski K. (2024) Nature Medicine https://doi.org/10.1038/s41591-024-03084-6

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