Operationalizing Cell & Gene Therapy: Challenges And Solutions

Cell and gene therapy has proven to be the future of cancer treatment, however, challenges remain in getting cell therapies to the market and into routine use to be widely adopted.

Cancer is the second most frequent cause of death worldwide with solid tumors such as lung, colon, prostate, and breast cancer serving as the major contributors to the high mortality rates¹.  The need for novel approaches to treat the disease has resulted in revolutionary advances in treatments, including therapeutic tools such as next-generation sequencing and cell and gene adoptive immunotherapies.  Once dubbed, “the cowboys of science,” innovative researchers have led us to fundamental scientific breakthroughs, which are moving the potential for cancer treatment forward with significant progress being made to effectively treat and control the disease. The National Cancer Institute projects that nearly 20.3 million more people worldwide are expected to survive cancer in 2026 compared to 2016².

Cell and gene therapy, at its most basic form, is the therapeutic delivery of nucleic acid into a patient’s cells as a drug to treat disease. Cell and gene adoptive immunotherapies are one of the most promising therapeutic modalities, which bring forth a new paradigm in cancer immunotherapy wherein a patient’s own T cells are bioengineered to express antigen receptors that identify, attach to, and subsequently kill tumor cells. These synthetically engineered T cells are better able to identify specific cancer antigens, which our bodies can have a difficult time recognizing as foreign cells. Adoptive T cell therapies that harness T cell receptors (TCRs) and chimeric antigen receptors (CARs) show great promise with distinct signaling properties and antigen sensitivities which provide an ultrasensitive modality of tumor-killing properties, providing tremendous opportunities to attack cancer. The therapy itself involves collecting T cells from the patient’s blood via leukapheresis, then modifying the cells to produce special structure of the CAR or TCR on their surface, and once enough cells have been created to launch a precise attack, returned into the patient. When these altered cells are reinfused into the patient, the new receptors enable them to latch onto a specific antigen on the patient's tumor cells and kill them.

Adoptive cell therapy has shown incredible success against blood cancers such as leukemia and lymphoma with at least two CAR-T cell therapies approved by the FDA in the United States: Novartis’ Kymriah for advanced or recurrent acute lymphoblastic leukemia and Gilead’s Yescarta for large B-cell lymphoma. Landmark approvals and clinical success of Kymriah and Yescarta have opened new and encouraging avenues for developers of cellular immunotherapies and are apparent when observing the number of clinical trials and companies in development for cell therapy products.

The current global cancer cell therapy pipeline includes approximately 1,483 active agents, 472 more than last year. Among the different cell therapy types, CAR-T class has the largest increase (290 agents this year versus 164 in 2019), whereas novel T cell approaches, such as CRISPR engineered T cells or γδT cells, and other cell therapies, such as macrophage-based therapies, have increased by 49 and 56 agents, respectively³. By 2025, the FDA expects to be receiving upwards of 200 INDs for cell and gene therapies each year as it is estimated they will be approving between 10 and 20 cell and gene therapies each year.

With such explosive growth and promise comes challenges, the treatment itself isn’t without its issues. Cell and gene therapies require operational excellence, complex manufacturing processes, enormous investing, and are accompanied by exorbitant price tags, just to name a few. While this is an incredibly exciting time and honor to be a part of this research for the future, the consistent and rapidly growing space leaves room for concern which we need to ensure we can keep up with our own rapid evolution.  This article aims to highlight some of the challenges with real-world evident solutions.

Operationalizing Cell Therapy

Volume of CGT Trials Versus Accessible Qualified Centers

Due to the complexity of cell therapies, the FDA currently mandates the collection and administration of products through a restricted and regulated program within certified centers by trained healthcare providers who adhere to risk evaluation and mitigation strategies (REMS) guidelines. This includes The Foundation for the Accreditation of Cellular Therapy (FACT) and The Joint Accreditation Committee ISCT-Europe & EBMT (JACIE), two accreditation providers that assure that the health care organization is qualified for patient care in this therapeutic setting.

Challenges:

1. The current and projected volume of cell therapy trials is not comparative to the number of accredited centers globally, leaving complex operational challenges for patients, sponsors, and hospitals.
2. While the treatment of cell therapy products must be mandated in certified centers by trained healthcare providers who adhere to REMS guidelines, procedures such as leukapheresis now overwhelm centers due to the volume of cell therapy trials. Standard procedures such as leukapheresis contribute to the operational burden on institutions and staff participating in autologous cell therapies.

Solutions: 

1. Choice companies now allow centers without formal accreditations such as FACT/JACIE to screen and perform apheresis while matching standards for qualification to that of FACT or JACIE organizations.

• The processes, procedures, and requirements for collection of starting material is at the discretion of the Sponsor and only in a clinical trial setting, however, allows for more sites to participate, increased patient screening, and enrollment while also alleviating centers’ workload of these already complex therapies.

2. Allow contract organizations such as the American Red Cross or Be The Match to perform apheresis. This helps to alleviate the burden most hospitals are facing with the overwhelming volume of cell therapy studies requiring apheresis.

Complex Patient Referral Pathway

Due to its complex nature, access to cell therapy is highly regulated and available for treatment only at certified centers as outlined above. This process can create a complex patient referral pathway, making for the widespread adoption of cell therapy challenging.

Challenge:

1. Due to the lack of accreditation, it is common that community centers are not involved in screening or referring patients for these potentially life-saving therapies, which leaves patients to be their own advocates for identifying cell therapy trials.

Solutions:

1. Inclusion of screening-only centers, sometimes known as satellite or alliance centers. These centers typically operate in small communities that have neither the capability to perform apheresis or treat patients but can screen patients and refer to centers with cell therapy capabilities.
2. This strategy requires training, contracting, screening protocols, regulatory oversight, and collaboration costs associated with additional sites while generating more than a 50% increase in patient identification and screening of some cell therapy trials.
3. Inclusion of community centers for screening and referral allows patients the potential to be treated with cell therapies while increasing the global footprint and availability.

Manufacturing

Manufacturing in cell and gene therapy is considered made to order as each treatment is patient-specific and manufacturing starts with very different and variable material, especially in an autologous process where every sample is received from a different patient.  The manufacturing process of autologous cell therapies requires apheresis, extraction of cells, transportation to a manufacturing facility, genetic engineering, and transportation of the finished product back to the treatment center where the personalized therapy is administered to the patient. This vein-to-vein time can range between three to six weeks depending on the product and company.

Challenges:

1. This highly personalized therapy creates a complex, multi-step process of generating autologous products which increases the risk of production failure, an event that delays, and in some instances denies access to the therapy.
2. The extended period of manufacturing and its delays can cause anxiety in patients awaiting treatment and sometimes may be unsuitable for patients with rapidly progressing disease.
3. Failed manufacturing or human error remind us that this is personalized medicine and cannot be easily replicated under urgent circumstances.

Solutions:

1. Companies are finding ways to safely accelerate the production time of manufacturing, including:

• Accelerated testing times and frequency.
• Enhanced caution to small deviations, data entries, and calculations that lead to batch errors potentially delaying release of treatment.

2. In-house manufacturing, rather than an outsourced CMO, can provide additional oversight into the manufacturing process itself, which allows for increasing readiness of products as well as control over logistical challenges that come with the vein-to-vein process.
3. Many of the logistical challenges associated with the complex manufacturing process of current autologous cell therapies will likely get addressed with allogeneic, off-the-shelf products, but this is a separate discussion requiring an in-depth analysis.

Patient Evaluation, Selection and Treatment

Identification of suitable patients for cell therapies can be challenging. Patient eligibility, including indication, haplotype and antigen-specific eligibility are required with autologous therapies and as community practices do not generally offer cell therapies, the timing of treatment may not be as clinically strategic as possible.

Challenges:

1. Identifying patients who meet eligibility requirements.
2. Due to the novel type of therapy, not all physicians are certain of cell therapy and its place in a patient’s treatment plan or its impact on further lines of therapy. This can potentially create uncertainty in physicians of how or when to appropriately treat patients.
3. Heavily pretreated patients can be weakened by progressing disease and prior therapies and thus be less-than-suitable patients for treatment as their disease has already become uncontrollable and unable to withstand side effects of therapy. Therefore, the eligible patient pool to qualify for these therapies can be limited to heavily pretreated patients with good performance status.

Solutions:

1. Patient engagement materials and education via scientific community sharing sessions from Sponsor-to-site-to community have proven to enhance patient recruitment and treatment while providing physicians a better consideration of how to incorporate these treatments into their traditional models.
2. Incorporating cell therapies into a patient’s treatment plan at initial diagnosis can provide the possibility of a more robust and durable response rather than once a patient has rapidly progressed after several lines of therapy.
3. Screening, enrolling and manufacturing at diagnosis allows the patient to have a cell product stored and ready for treatment if a first or second line of therapy has been exhausted.

Volume of Cell Therapy Treatments Versus Available Staff

As with introduction of any new advanced therapy, additional expertise is required to enable successful implementation. With the success of cell therapy comes the obvious challenge of available staff and personnel at both the participating centers to the companies implementing them.

Challenges:

1. Scientific and clinical development has outperformed the training of cell therapy professionals to address the additional work demand.
2. External personnel will be needed to provide expertise that is not available within participating hospitals in the management of cell therapy products.

Solutions:

1. Creation and implementation of cell and gene specific education programs for both Sponsors and institutions.
2. Modifying and training for existing staff members to specialize in cell and gene therapies.
3. Assessing the necessary end-to-end expertise and comparing it to the current internal proficiency will highlight strengths and significant shortfalls.

Conclusion

Cell and gene therapy has proven to change the way cancer is treated. While many challenges remain, and not identified in this article, physicians, patients, and investors are convinced that cell therapies are a revolutionary cancer treatment. This is an incredibly exciting therapy to add to a healthcare provider’s arsenal and give hope to patients who would otherwise be left with no alternatives. However, we will have to continue moving at the speed of sound in developing the capability to deliver these therapies.

References

1. Ginn SL, Amaya AK, Alexander IE, Edelstein M, Abedi MR. Gene therapy clinical trials worldwide to 2017: An update, Journal of Gene Medicine: doi.org/10.1002/jgm.3015, 2018
2. Cancer Statistics, National Cancer Institute: www.cancer.gov/about-cancer/understanding/statistics, 2018.
3. Yu JX, Upadhaya S, Tatake R, et al. Cancer cell therapies: the clinical trial landscape. Nature Reviews Drug Discovery 19, 583-584, 2020.
4. Titov A, Valiullina A, Zmievskaya E, et al. Advancing CAR T-Cell Therapy for Solid Tumors: Lessons Learned from Lymphoma Treatment. Cancers 12(1), 125, 2020