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Cytotherapy Corner - January 2023


Donald G. Phinney, PhD

Senior Editor
Department of Molecular Medicine
UF Scripps Biomedical Research
Jupiter, FL, USA


            As we enter 2023, I want to express my appreciation to the Cytotherapy team and members of the ISCT for their continued efforts to support the mission of the journal and improve its impact in the fields of cell and gene therapy.  I am optimistic the journal will continue its unprecedented growth in 2023. 

In this issue of Cytotherapy Corner, I want to highlight a manuscript in the December 2022 issue by Thielen et al., that describes a cost-based pricing model to predict market prices for cell and gene therapies (CGTs). As new CGTs gain market approval and existing therapies see expansion in their prescribed use, issues surrounding the accessibility of these groundbreaking therapies has come to the forefront due to their prohibitive costs.  In their analysis, the authors use two products, Zolgensma and Libmeldy as case studies. Zolgensma (onasemnogene abeparvovec) is a non-replicating, self-complementary, adeno-associated viral vector (scAAV9) that encodes a fully functional survival motor neuron 1 (SMN1) protein and is approved in the U.S. and Europe for treating pediatric patients with spinal muscular atrophy.  Libmeldy (antidarsagene autotemcel) is a cryopreserved autologous CD34+ cell-enriched population transduced ex vivo with a lentiviral vector encoding the human arylsulfatase-A (ARSA) gene and is approved in Europe for treating patients with early onset metachromatic leukodystrophy (MLD).

In their analysis, the authors employed a pricing model that included research and development expenses, the number of eligible patients that may benefit from the drug during its patent lifetime, the cost to manufacture the drug, and its profit margin. These parameters were then input into deterministic sensitivity and scenario analyses to assess impacts on the calculated price. This analysis revealed that different input parameters yielded different impacts on pricing for each product. For example, R&D expenses had a larger impact on pricing for Libmeldy compared to Zolgensma, while the number of eligible patients and profit margins most significantly influenced the pricing of Zolgensma. Moreover, assumed R&D expenses were found to significantly influence price, especially when the number of eligible patients was low. Notably, the authors excluded the contribution of public financial contributions to the development of each drug, which in some instances may be substantial.  While manufacturing costs also contribute significantly to product pricing, the authors noted that little information is available on the cost of CGT manufacturing itself and on how strategic decisions in manufacturing development influence cost.  Most importantly, the estimated prices for both products were substantially lower in this study as compared to their list prices. Overall, the paper represents an important contribution toward efforts to develop fair pricing metrics for approved CGTs.      

The January 2023 issue includes a paper from the Immuno-Gene Therapy Committee of the ISCT authored by Gustafson et al. that describes the rapid pace of advancements of cell and gene therapies for the treatment of cancer. The manuscript focuses specifically on four platforms, CAR T cells, engineered T cell receptors, NK cells, and point-of-care manufacturing. The authors provide an overview of the CAR T field, highlighting existing approved products, lessons learned from their use in patients, and how these lessons are shaping the future directions of the field. The latter includes the development of dual-targeting CAR T cells to avoid immune escape, overcoming T cell exhaustion, avoiding CAR T fratricide, and minimizing toxicity associated with CAR T administration. Next, the authors discuss the state of the art in the field of T cell engineering, summarize clinical results from these therapeutics, and describe ongoing gene editing approaches to development engineered T cells with greater potency and selectivity and reduced toxicity. The utility of NK cells as cancer therapeutics is then highlighted, and the authors offers an excellent discussion on the different approaches to generate NK cells, which range from peripheral blood to embryonic stem cells, gene editing strategies that are being employed to generate CAR NK cells, and limitations associated with the use of native and engineered NK cells in patients. The section concludes with a discussion about how efforts to manipulate NK cell metabolism are being exploited to enhance their activation and persistence in vivo. Lastly, the authors discuss point-of-care manufacturing, which has important ramifications on the availability and cost of products. The authors describe important advancements made in manufacturing over the past decade and obstacles to implementing a POC model, including the readiness of institutions and regulatory authorities to pursue these goals. Overall, the article is highly informative, provides a unique perspective on the challenges in delivering CGTs to cancer patients, and as such nicely compliments the study by Thielen et al. in the December issue.


Happy reading.