Committee Spotlight: ISCT Immuno and Gene Therapy Committee

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by
Gaurav Sutrave, B Sc(Med), MBBS, PhD
Staff Specialist Haematologist
Westmead Hospital
Sydney, Australia

The clinical success of CD19 specific chimeric antigen receptor (CAR) T cells and subsequent regulatory approvals for their use in the treatment of relapsed and refractory B cell malignancies has led to an explosion of research in the field of immuno-, cell and gene therapy. This has led to rapid advancements being made to broaden applications outside of hematological malignancy, such as intreatment of solid organ tumors as well as in some non-malignant conditions. Moreover, there is a push to develop more efficient, safer and cost-effective manufacturing methods to improve accessibility of these products. The gradual incorporation of these immuno-, cell and gene therapies into the standard of care, combined with the constant evolution of the cutting edge of cell and gene therapy clinical trials, has highlighted a series of scientific, manufacturing and logistical challenges that face the field. To address these needs, the ISCT Immuno- and Gene Therapy (IGT) Committee has been established to regularly review the status of the immuno- and gene therapy field in order to identify the key issues that need to be addressed so as to continue advancing and enabling greater utilization of cellular and gene therapies. The IGT Committee is currently co-chaired by Dr. Sandeep Soni (Executive Medical Director, Clinical Development, CRISPR Therapeutics Inc / Clinical Associate Professor, Division of Pediatric Bone Marrow Transplant, University of California, San Francisco) and Dr. Michael Gustafson (Scientific Director Nyberg Human Cellular Therapies Laboratory and Associate Professor, Laboratory Medicine and Pathology, Mayo Clinic, Phoenix, Arizona), and has members at all career stages with representation from all across the globe. The ISCT IGT Committee has sought to achieve its goals through several means including assisting with the planning of the ISCT annual meeting scientific program through organizingn round table sessions that have been particularly well received. The identification of the critical role of a skilled cell therapy laboratory workforce has prompted the ISCT IGT Committee to initiate workforce training programs at several levels to assist with not only professional development of scientists within the field, but also to help train the upcoming generation of immuno- and gene therapy leaders. Finally, the IGT Committee also has undertaken to publish a series of position and review papers to engage scientific discourse not only within the ISCT but also more widely within the immuno- and gene therapy community.

Over the last 12 months, the ISCT IGT Committee has coordinated the publication of several reviews in the journal Cytotherapy to highlight the most recent advances and challenges confronting the immuno- and gene therapy field. The most recent of these was published in the January 2023 issue by Gustafson et al [1], providing an overview of the current emerging cell and gene therapy platforms for the treatment of cancer. In this paper, the authors highlight the current state of the field in hematological malignancies, outlining the impressive and durable clinical responses from the use of CAR T cells as well as the advances in toxicity management leading to improved tolerability of therapy. However, a similar degree of potency and safety has not been universally demonstrated in CAR T cells targeting solid organ tumors. This disparity is due to a variety of different factors including immunosuppressive tumor microenvironment leading to CAR T cell exhaustion, tumor heterogeneity leading to difficulties with ideal target antigen identification and potential “on-target, off tumor” toxicity, and poor CAR T cell trafficking to tumor sites following systemic infusion. In identifying these scientific barriers, the authors have further outlined the current research being conducted to enhance the efficacy of cellular therapies for solid organ tumors including combinatorial CAR systems, intra-tumoral CAR T cell delivery, utilization of alternative tumor targeting systems (such as transgenic T cell receptors) or cell effectors (such as natural killer cells) and the use of incorporated safety systems to ensure the elimination of infused gene modified cell therapies in the event of unacceptable toxicity. Finally, the authors explore recent advances in CAR T cell manufacturing processes to improve access and cost-effectiveness of advanced therapeutic medicinal products (ATMP). Specifically, the authors focus on the emerging potential of point of care (POC) manufacturing, highlighting the currently available technologies, the position of regulatory bodies with regards to POC (as opposed to centralized) manufacture of ATMPs, and the potential approaches to address local institutional barriers before such manufacturing methodologies can be applied in practice.

While POC represents one of the potential frontiers in the cell and gene therapy field, the current standard involves centralized cell therapy product manufacture, with local institution cell processing facilities (CPF) responsible for the handling and safety of the product as it is transported to and from the manufacturer and released to the patient for infusion. To ensure the integrity of this process, the CPF needs robust standard operating procedures, an appropriately trained and staffed workforce, and comprehensive logistics planning. The proliferation of commercial products, industry sponsored clinical trials, and investigational cell therapy products has the potential to place particular strains on CPF due to differences in terms of handling, processing and transport required of both the starting cellular material as well as the final cell therapy product. As a means to promote cross-facility sharing of knowledge and experience to address these emerging challenges, Dr. Patrick Hanley, the previous ISCT IGT Committee co-chair, in conjunction with Dr. Gustafson, coordinated the publication of a mini-series on supporting externally manufactured cell and gene therapies in the January 2022 issue of Cytotherapy [2]. In this mini-series, invited authors from the Immune, Progenitor and Cell Therapeutics (IMPACT) Laboratory at the Mayo Clinic in Rochester, Minnesota [3]; the Cellular Therapy Laboratory (CPL) at the New York Presbyterian Columbia University Irving Medical Centre [4]; and the Cell and Molecular Therapies Laboratory at the Royal Prince Alfred Hospital, Sydney, Australia [5] shared their combined experiences in the development of scalable processes in order to ensure compliance with the regulatory requirements to allow for the efficient and safe handling and transport of the ever expanding range of cell therapy products. Perhaps more importantly, in this mini-series, Bersenev et al [6] reported on the outcomes of an ISCT IGT Committee initiated worldwide survey on the approaches currently being undertaken by hospital-based CPFs to incorporate externally manufactured cell therapy products, with a particular focus on those utilized in clinical trials. The survey revealed some interesting trends, specifically the generally limited role most CPFs play in reviewing agreements between cell therapy product manufacturers and other units within the hospital. In spite of this limited engagement, 83% of CPFs expressed a reasonable degree of institutional support (including for additional staff), although only 54% of CPFs actually hired additional staff. This was in spite of 86% of respondents requiring the incorporation of additional processes and procedures in their practice to facilitate the conduct of new cell therapy clinical trials. This survey was the first to report CPF practices and provides a valuable resource to allow for standardization of practices to incorporate new cell therapy trials across different CPFs.

The advances in gene modified cellular therapies have been paralleled by a similar degree of evolution within the field of gene therapies. The advent of novel gene editing technologies, in particular clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9, has led to increased research into the application of these tools in the correction and treatment of monogenic disorders. Just as with cellular therapies, some of these gene therapy-based treatments have proved revolutionary for disorders such as hemophilia B, thalassemia and spinal muscular atrophy. The subsequent regulatory approvals for these therapeutics have unearthed a plethora of challenges relating to optimization of product manufacture, creation of assays to ensure safety and efficacy and ensuring cost-effective delivery to patients who stand to benefit. To highlight the current landscape of gene therapies, the ISCT IGT Committee has just completed a mini-series in gene therapy to be published in the upcoming March 2023 issue of Cytotherapy. Compiled by IGT Committee co-chair Dr. Sandeep Soni and Dr. Paula Rio, this mini-series consists of a set of articles outlining the advances in base editing technologies (including the emergence of cytosine and adenosine base editors), their potential clinical applications and the current barriers that need to be addressed to facilitate more widespread adoption of these gene therapies. The mini-series also reviews the critical role of the delivery platforms and the current optimization steps being undertaken to enhance the efficacy of gene therapies.

The ISCT IGT Committee is currently undertaking several other initiatives in addition to the aforementioned published survey. One of the key areas of need highlighted by this survey of CPFs is the critical need for ongoing workforce development to ensure the effective implementation of scientific advances in the cell therapies field within the regulatory framework within which these products are utilized in a clinical context. The ISCT IGT Committee is championing several such workforce development initiative at all levels, including contributing members to the ISCT Early Stage Professional (ESP) Mentoring Program as well as developing a pilot high school workshop in cell and gene therapy. These enterprises are geared towards training the next generation of leaders in the field and enhancing the quality of the emerging workforce to deal with evolving challenges unique to immuno- and gene therapies. The ISCT IGT Committee members are also involved in the review process for abstracts submitted to the annual meeting in the cell and gene therapy category to ensure a varied and high-quality scientific program.

As the number of immuno- and gene therapy products continues to expand, novel and complex challenges will continue to emerge. The ISCT IGT Committee aims to play an important role in identifying pathways to address these issues in order to advance and enable greater access to more effective immuno- and gene therapies. More information regarding the IGT Committee and activities can be located on the ISCT Committee website . Expressions for interest to join the Committee or be involved its activities are welcomed and can be directed to Lexis Kepler (lexis@isctglobal.org).

References

Gustafson, M.P., et al., Emerging frontiers in immuno- and gene therapy for cancer. Cytotherapy, 2023. 25(1): p. 20-32.
Hanley, P.J., A. Bersenev, and M.P. Gustafson, Delivering externally manufactured cell and gene therapy products to patients: perspectives from the academic center experience. Cytotherapy, 2022. 24(1): p. 16-18.
Wiltshire, T.D., et al., Management of externally manufactured cell therapy products: the Mayo Clinic approach. Cytotherapy, 2022. 24(1): p. 19-26.
Jackson, M.R., Accommodating clinical trials and other externally manufactured cellular therapy products: challenges, lessons learned and creative solutions. Cytotherapy, 2022. 24(1): p. 37-44.
Velickovic, Z.M. and J.E.J. Rasko, Establishing a robust chimeric antigen receptor T-cell therapy program in Australia: the Royal Prince Alfred Hospital experience. Cytotherapy, 2022. 24(1): p. 45-48.
Bersenev, A., M.P. Gustafson, and P.J. Hanley, ISCT survey on hospital practices to support externally manufactured investigational cell-gene therapy products. Cytotherapy, 2022. 24(1): p. 27-31.