Global Head of Research of Kite Pharma Unveiled the Key Elements to Success in Adoptive Cell Therapy

As the Cell & Gene Therapy Research & Development Congress Asia 2023 kicked off in Taipei, Taiwan, leaders, academicians, and researchers around the world shared their insights and recent breakthroughs made in the field, including the emerging advances in the field of cell and gene therapy, the regenerative potential of stem cells, the application of T-cells and CAR-T in the field of immuno-oncology, and more.

Factors Affecting Therapeutic Index of Cell Therapies

Day one of the conference started with a keynote address themed “Contextual Regulation of Cell Function for Adoptive Cell Therapy” by Dr. Franco Marincola, global head of research of Kite Pharma, sharing the challenges and opportunities in the R&D field of cell and gene therapy. At the beginning of his speech, Dr. Marincola introduced the concept of the therapeutic index, pointing out that the effectiveness and safety of adoptive cell therapy (ACT) need careful quantitative assessment. Specifically, four therapeutic indicators should be taken into account, including persistence, trafficking, engagement, and resilience to immune suppression.

Using CAR-T cell therapy such as Axi-cel as an example, Dr. Marincola stated that the persistence (fitness) of T cell products is an important factor for predicting the long-term therapeutic efficacy. Trafficking of T cells into tumors is also a factor to be considered, as T cells have to be localized at the site of the tumor so as to perform their therapeutic functions. Apart from being delivered to the tumor, T cell therapy cannot work effectively in the case of immune-excluded tumors in which T cells are unable to penetrate the tumor core. Resilience to immunosuppression in the tumor microenvironment is also crucial for T cells to show sufficient anti-tumor activity.

Key Elements for Successful Adoptive Cell Therapy

Dr. Marincola emphasized that biological, technical and practical considerations are all of profound importance for creating a successful adoptive cell therapy. Biological issues cover optimal target selection, fitness of T cell product, polyfunctionality and selective targeting against disease-affected tissues (context-dependent adaptability). Technical factors involve real-time remote control of the effectiveness and toxicity of ACT products in vivo, T cell multiplexing and ensuring the feasibility of the treatment. Regarding practical requirements, Dr. Marincola pointed out that the flexibility of targeting, simplification of production, as well as simplification of delivery, are some crucial points for achieving therapeutic success.

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Combating a Rare Genetic Metabolic Disorder with ex vivo Gene Therapy

Following Dr. Marincola’s keynote address, the second presentation of the day was delivered by Dr. Christine Duncan, MD, principal investigator at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, with an emphasis on ex vivo gene therapy for children suffering from adrenoleukodystrophy (ALD), highlighting efficacy and safety findings from recent clinical trials.

Caused by mutation in the ABCD1 gene on the X chromosome, ALD is a metabolic disease that affects the brain, spinal cord, peripheral nerves and the adrenal cortex. The mutation leads to the accumulation of very-long-chain fatty acids (VLCFA) in tissues throughout the body. Excess VLCFA will subsequently cause damage to the adrenal gland and neurons of the brain and adrenal glands, causing adrenal insufficiency and debilitating nervous system effects. 

It is estimated that ALD affects 1 in 17,000 newborns (1 in 21,000 males) in the U.S., and the disease has 4 forms of severity, ranging from asymptomatic to cerebral ALD (cALD), the most severe one that causes severe neurodegenerative decline. It is also noteworthy that about 35 – 40% of affected males may ultimately develop cALD and the disease can aggravate from an asymptomatic state to a major functional disability (MFD) over a period of 24 months. 

Therapeutic Options Available for ALD

Dr. Duncan then mentioned two important therapeutic options for ALD that can effectively stop disease progression, namely, allogeneic hematopoietic stem cell transplantation (allo-HSCT) and gene therapy. Allo-HSCT involves donation of stem cells from an allogeneic donor, followed by preparing the patient with myeloablative chemotherapy and finally stem cell infusion. Despite providing significant survival benefits for patients, allo-HSCT is a risky therapeutic approach as it is associated with life-threatening complications including graft failure, graft versus host disease (GVHD), and treatment-associated infections. Besides, it is only effective in controlling early-stage disease and cannot reverse existing symptoms.

Regarding gene therapy, Dr. Duncan focused on Elivaldogene automacel (Eli-cel, later commercialized as Skysona) in her presentation. In particular, she highlighted the two clinical trials of Eli-cel: ALD-102 (started in 2013) and ALD-104 (started in 2019). In terms of efficacy, 91% of patients who received Eli-cel in ALD-102 met the primary endpoint of MFD-free survival at 24 months. For the safety profile, no case of GVHD, graft failure or treatment-related mortality were reported. In spite of 3 cases of myelodysplasia (out of 67 patients) were found and such incidents once caused the FDA to place a clinical hold on Eli-cel trials in 2021, the therapy earned unanimous support from FDA Advisory Committee in June 2022 and finally won FDA approval in September. 

Future Challenges of ex vivo Gene Therapy for ALD

However, with a record-breaking price of $3 million per treatment, Skysona’s exorbitant treatment cost is still a deterrent to many. Also, the therapy is currently only available at a limited number of sites in the United States. In spite of these substantial challenges, Dr. Duncan believes that the commercialization of Skysona not only provides more choices on ALD treatment options but also allows for informed decision-making for patients and their caregivers.

Author

Richard Chau