Evolving the Delivery of CAR T-Cell Therapies to the Outpatient Setting

Abstract: The availability of adoptive cell therapies allows clinicians to genetically reprogram patients’ own immune cells to find and attack cancer cells throughout the body. Chimeric antigen receptor (CAR) T-cell therapy—a type of adoptive cell immunotherapy—has led to remarkable patient outcomes and has the potential to transform cancer treatment. It has started as an exclusively inpatient procedure but is evolving into the outpatient care arena. However, before cellular therapies become standard outpatient procedures, many critical issues will need to be addressed, including coordination of care, availability of specific resources, education of patients and caregivers, and toxicity management—both clinical and financial toxicity.

Acknowledgments: Thanks to the team at The US Oncology Network and McKesson, including Dr Marcus Neubauer, Jill Maddux, and Sharon Munroe.

Chimeric antigen receptor (CAR) T-cell therapy has its origins in the early work in immunotherapy, dating back to 1893 when William Coley recognized the potential of employing the immune system in treating cancer by injecting streptococcus into an inoperable sarcoma, which resulted in tumor shrinkage.¹ A significant milestone in the development of adoptive cell therapies occurred in 1987 with the discovery that lymphocytes in metastatic melanoma could be transformed by IL-2.²  The use of adoptive cell therapies was first described in 1988, but the critical improvement occurred in 2002 with the introduction of an immunodepleting preparative regimen given before the adoptive transfer, resulting in improved repopulation of anti-tumor T cells.³

The development of CARs was originally considered as a conduit for transplantation in B-cell leukemias and lymphomas.⁴ The first successful CAR therapies were directed against B-cell hematologic malignancies, targeting the CD19 marker, which is highly specific to B-cells including those transformed to lymphoma and leukemia.⁵ Currently, 2 CAR T-cell products are approved by the Food and Drug Administration (FDA) in oncology: (1) tisagenlecleucel (Kymriah; Novartis) is indicated for patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse and in the treatment of adult patients with relapsed or refractory (R/R) large B-cell lymphoma after 2 or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma⁶; and (2) axicabtagene ciloleucel (Yescarta; Kite) for the treatment of adult patients with R/R large B-cell lymphoma after 2 or more lines of systemic therapy, including DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.⁷ While these 2 commercially available products target B-cell malignancies, clinical trials are being conducted in other hematologic malignancies as well as solid tumors, offering promising new treatment options for patients with cancer and potentially other diseases. 

CAR T-Cell Therapies Now 

CAR T-cell therapy has succeeded where conventional therapies have failed. One remarkable example is the complete remission rate in pediatric and young adults with R/R B-cell ALL treated with Kymriah reported at 83% in the ELIANA trial (NCT02228096) with subsequent follow-up reporting an 81% overall remission rate.⁸ However, the early clinical trials leading to the current FDA-approved products were conducted in bone marrow-transplant centers to provide close monitoring of patients due to the potentially lethal toxicities of these therapies. Patients may experience an exaggerated immune response known as cytokine release syndrome (CRS), which could result in death if not diagnosed and treated promptly. Safety information for both commercially available products recommends frequent monitoring of patients post-infusion within the first week and up to 4 weeks post-infusion.^6,7 Inpatient hospitalization for this period is not required unless complications occur. Some outpatient hospital departments have reported administering treatments while still permitting close monitoring of patients. 

The initial clinical trials for the FDA-approved cellular therapies were conducted in academic centers, but the future administration of these therapies and the future conduct of clinical trials need not be restricted to this setting. Not all CAR T-cell products are the same and therefore have varying toxicity profiles. A true assessment of the appropriate setting for the administration of cellular therapies will be dependent upon the ability of the treatment center to meet the specific safety requirements for the safe administration and monitoring of patients.

While many oncologists view CAR T-cell therapies as a new and “potentially game-changing approach to treatment,” in one 2017 survey of 338 oncologists, 80% reported they would send some or all of their eligible patients to academic centers.⁹ Twenty-four percent of respondents in the same survey believed that CAR T-cell therapies could be delivered safely in a community setting, as all adoptive cell therapies are not equal and do not exhibit the same side effect or toxicity profiles. In a May 2018 survey of physicians in The US Oncology Network, approximately 70% confirmed a high-level interest in learning more about the requirements and support needed for their practice to become a CAR T-cell infusion center and/or CAR T-cell research center.¹⁰  

The Path Forward for CAR T-Cell Therapy

Adoptive cell immunotherapy was named the ASCO 2018 Advance of the Year.¹¹ Can these new therapies be safely administered in a community setting? They can be as long as there is proper site planning, care coordination, staff education, patient selection, and patient/caregiver education. Clinical trials are being designed to specifically test the feasibility of outpatient CAR T-cell therapy. At the same time, community oncologists are gaining access to administer the FDA-approved products, many of which are affiliated with transplant centers.  

For many oncologists, the preparation to administer CAR T-cell products is similar to the model used to prepare for outpatient stem cell and bone marrow transplant programs. Building upon that model, community-based practices have demonstrated their ability to coordinate interdisciplinary care and close monitoring and follow-up of patients, making them well-positioned to offer CAR T-cell therapies. It is not anticipated that all community practices will have the ability or desire to develop the infrastructure to meet the complex care requirements for these patients, however, many community practices are positioned to offer clinical trials for their patients on an outpatient basis. Contributing to this shift to an outpatient model is the knowledge gained from the existing FDA-approved products, new therapies in clinical trials with less toxic side-effect profiles, and the next generation of CAR T-cell therapies referred to as “off-the-shelf” products from healthy donors. 

Practices in The US Oncology Network are actively preparing for the launch of cellular therapy clinical trials primarily treating patients in the outpatient setting. In addition, many physicians associated with transplant programs have completed or are completing manufacturer-certification programs to administer the currently available commercial products.

Making CAR T-Cell Therapy More Accessible

Basic Requirements and Necessary Infrastructure

Based on the knowledge gained from working with centers that have been approved to administer the commercially available CAR T-cell therapies and in preparation to meet sponsor requirements for outpatient clinical trials for cellular therapies, we provide a detailed overview of how facilities can self-assess and prepare to deliver CAR T-cell infusion. The list in Box 1 identifies the minimal requirements for consideration by community practices. Expansion upon these requirements will be provided later. 

As community practices prepare for the eventual outpatient administration of these cellular products, they will need to meet these requirements to build the necessary infrastructure to meet the complex care requirements for these patients and their caregivers. Community oncologists are gaining experience with these therapies in their collaboration with transplant centers, contributing to the evolution to an outpatient model for care. 

Steps in the CAR T-Cell Therapy Patient Journey 

It is helpful to first understand the patient journey chronologically for those receiving CAR T-cell therapy. The preparation of the patient and caregiver requires close collaboration by several members of the health care team (Figure 1). The process involves the following steps^12,13:

1. Leukapheresis or lymphocyte collection at a blood center, clinic, or infusion center.
2. Transport of the collected cells to a laboratory for the cells to be genetically modified.
3. Cell engineering, which can take anywhere from 10 days to several weeks.
4. Patient conditioning or lymphodepleting chemotherapy.
5. CAR T-cell infusion.
6. Patient monitoring and follow-up.

Most community oncology practices will need to identify a local center for leukapheresis for the first step in the process. Coordination with a local blood center or hospital-based apheresis unit will be required for the white blood cell collection. Apheresis units must have policies and procedures in place for the collection, packaging, and shipping of the cells. Cells are then sent to the manufacturer’s laboratory where they will be modified and then expanded to the appropriate number of cells. Many factors can impact how long the expansion of cells will take, but it is estimated to take approximately 2 weeks.  

After sufficient cell expansion, the patient will receive a lymphodepleting chemotherapy regimen to foster the engraftment of the new T cells to be administered. Following this low-dose chemotherapy regimen, the patient’s modified T cells are reinfused generally as one dose, but this may be manufacturer or protocol specific if the patient is participating in a clinical trial. Following administration, the follow-up phase begins.  

Post-infusion, close monitoring of the patient is required to assess for any complications. CAR T-cell therapies are not all the same and may have varying degrees of side effects and toxicities. Health care providers, patients, and family/caregivers will need to fully understand the specific side-effect profile for the CAR T-cell product administered. Caregivers should receive education to assess for changes in cognition and other potential neurological toxicities. The seriousness of any toxicity should be reported early and evaluated immediately, as the intensity of the toxicity can escalate quickly in some cases. Close care coordination with the patient, family/caregivers, and health care team is absolutely essential.  

Patients who receive CAR T-cell therapy will require 24-hour access to clinicians who can diagnose and begin early management of any complications. Patients and caregivers should have access to on-call physicians who have been trained in managing cellular therapies. If a patient develops serious side effects, hospital admission may be required. The potential for a hospital admission should be planned, so the patient can be fast-tracked to a designated bed. Specific medical specialists with knowledge of CRS and neurologic toxicities associated with these therapies should be available, including oncologists, neurologists, and possibly intensivists. Appropriate pharmaceutical support will also be required to care for patients with serious side effects and/or toxicities.

Similar to the follow-up conducted for bone marrow transplant patients, patients receiving cellular therapies will be followed as part of an ongoing registry to monitor their outcomes.  In the approval letters from the FDA, both Novartis and Kite are required to conduct follow-up with patients for up to 15 years as part of a post-marketing observational study to monitor long-term safety and the risk of secondary malignancies.^14.15 The follow-up may be integrated into an existing survivorship program. Survivorship care planning is often provided by advanced practice providers and include a review of treatments, ongoing assessments, and care planning customized to the needs of the patient.

Standards and Expanded Guidance for Facilities

The Foundation for the Accreditation of Cellular Therapies (FACT) has published Standards for Immune Effector Cell to promote quality practice in immune effector cell administration. These standards address care along the patient journey from donor selection and management, the administration of the cellular products, early management of complications, and evaluation of outcomes.¹⁶  The FACT website supports the premise that CAR T-cell therapies may be provided in various settings by stating: “These Standards are intended to be flexible to accommodate various models of patient care and use of cellular therapy products.”¹⁶

The FACT standards provide a blueprint to help anticipate the care required along the patient journey. Again, appropriate preparation of health care professionals and facilities as well as education of patient and caregiver(s) is essential. Navigation services or care coordination among various members of the health care team and potentially different care settings will be of paramount importance. In addition to FACT, other professional organizations have said in conversation that they are developing guidance on T-cell therapies, including the American Society of Hematology, American Society for Blood and Marrow Transplant, American Society of Gene and Cell Therapy, and International Society for Cellular Therapy, among others.

We have compiled a list of key items and standards for interested practices to consider based on available sources and field experience. 

1. Physician engagement. Highly engaged physicians with cellular therapy expertise are the core of every CAR T-cell program. Each practice should identify a lead physician to serve as the clinical program director, as outlined in the FACT Standards,¹⁶ Patients and caregivers need to be provided 24/7 access to on-call physicians specializing in the specific therapeutic disease area and trained in the management of patients receiving cellular therapies. Physicians may need to provide prompt evaluation and management of anticipated complications of cellular therapy including CRS and neurologic toxicities, among others.     
2. Development of written policies and procedures.  Policies and procedures must cover critical aspects of operations and management, including a quality management plan for all potential and planned services.¹⁶ 
3. Institutional Biosafety Committee. IBCs are required to assess risks associated with genetic modifications and experimental procedures as well as to address occupational and environmental safety. Requirements for developing an IBC are published on the National Institutes of Health website.¹⁷ Practices can institute their own IBC or access a commercial IBC to provide support to sites conducting research involving recombinant DNA (genetic engineering) to meet federal guidelines.
4. Manufacturer Certification.  For commercially available products, manufacturers will outline their specific certification requirements. 
5. Risk Evaluation and Mitigation Strategies (REMS).  In approving CAR T-cell products, the FDA has mandated REMS programs to reduce the risks of CRS and neurological toxicities.  The mitigation strategies include: (1) REMS training specific to the product and the appropriate management of the risks of CRS and neurological toxicities, and (2) that hospitals and clinics are specially certified and have immediate access to tocilizumab.^{18, 19}
6. Space. Due to the frequency of follow-up visits, space for the patient and caregiver must be considered. The infusion room may be adequate for the administration of the lymphodepleting chemotherapy and the subsequent administration of the genetically modified cells, but alternate space for the post-infusion observation will need to be considered to monitor any potential side effects. FACT outlines specific standards for the clinical unit.¹⁶  Also ensure that you have the proper storage capabilities for the shipping container that delivers the cryopreserved CAR T-cells from the lab. Generally, the delivery is coordinated for prompt administration to the patient, but cell storage must be planned. For clinical trials, the cellular product is considered an investigational product and must be stored and secured per FDA regulations.
7. Clinical competency. For use of both commercial and investigational products, each member of the care team should receive training. FACT Standards outline the training and competency requirements for all personnel including the physician serving as clinical program director, attending and consulting physicians, advanced practice providers, nurses, pharmacists, and other potential members of the care team.¹⁶ For clinical research protocols, adherence to the specified training of the protocol will also be required. In addition, members of the care team must be skilled in interdisciplinary team-based care, communication with other specialty providers, and care coordination across settings.

Patient-Specific Considerations and Patient Education

The decision to recommend CAR T-cell therapy is not solely dependent on patient diagnosis but should consider other variables as well, including family support structure and the patient’s ability to adhere to the treatment plan and follow-up requirements. Many of the same patient and family considerations used in the care of patients undergoing bone marrow transplants apply to patients preparing to receive cellular therapies. A patient navigator or social worker will be helpful to coordinate care with other important variables including:  

• Housing. Patients who live more than a 30-minute driving distance from their practice/treatment facility may be required to secure temporary housing for up to 4 weeks post-infusion so they can be closely monitored for potential adverse events. 
• Transportation. Patients may require assistance with transportation to and from the practice/treatment facility for the therapy itself and for frequent follow-up appointments. 

Health care providers should discuss therapy protocols extensively with patients and their caregivers, including how to recognize the early signs of potential treatment toxicities and anticipated side effects. They should be well informed of the planned treatment schedule including cell collection, the conditioning regimen, cell infusion, and the frequent monitoring schedule. 

Discussing the financial implications of CAR T-cell therapy with patients and families is an imperative. Wth the cost of the commercial products ranging between $373,000 to $475,000, financial counseling will be needed to help the patient and family understand the patient’s benefit plan and to access manufacturers’ patient assistance programs. It should be noted that this cost is only for the re-engineering of the cells and does not include the cost for cell collection, the conditioning regimen, or any costs associated with professional services of the physician or fees for a possible hospital stay, if required. Financial counselors can assist with accessing manufacturers’ patient assistance programs. Practices within The US Oncology Network have numerous resources available for patients and their caregivers such as social workers in addition to financial counselors who locate sources for grants and services.

Using Technology to Simplify CAR T-Cell Processes

Technology used every day in the community practice, like electronic health records (EHRs) and patient portals, can be leveraged to support the care of patients receiving cellular therapies. Customization to the EHR to provide structured data fields can efficiently support monitoring and data collection of patient outcomes. Structured data fields simplify data reporting to manufacturers and disease registries, so an EHR system with those capabilities is essential. McKesson’s iKnowMed^SM captures comprehensive patient outcome information, tracking diverse and granular levels of clinical data at the point of care.²⁰ Technologies such as apps and EHR-connected patient portals like My Care Plus enable communication with providers and tracking of the patient experience, and can be used to collect patient-reported outcomes.²¹

The care of patients receiving cellular therapies requires coordination among several entities, including the manufacturing facility and health care providers at the community practice, hospital, or leukapheresis center. Cryopreservation logistics partners such as Cryoport, Vineti, and TrakCel are examples of data platforms created to manage the end-to-end logistics and provide a vehicle for communication and harmonization of the multiple steps involved in providing individualized cell therapies.^22-24 As gene and cellular therapies continue to develop and expand to more disease states, these software platforms may become a necessity to monitor the chain of identity and chain of custody for such a complex supply chain with multiple touchpoints.

Future Concerns

Cost will likely remain one of the key challenges in CAR T-cell therapy. The fee for the re-engineered cells is only one part of the fully burdened costs to the patients and the payers. There may be a tipping point as more indications are approved and patient eligibility broadens. As the care delivery models for cellular therapies expand to include more community-based providers, will there be sufficient manufacturing facilities to meet the demand? Cell manufacturing can take from 2 weeks up to 22 days from receipt to shipment of cells. Potentially, off-the-shelf CAR T-cell products may offer an alternative to the current autologous model. The currently available CAR T-cell products are for patients with relapsed and refractory disease. Many more clinical trials will be needed to identify the proper positioning of them in the earlier treatment setting. Lastly, the effectiveness of adoptive cell therapies in treating solid tumors remains an area for future research.

Conclusion

For select hematologic malignancies, CAR T-cell therapy has succeeded where conventional therapies have failed. Community-based physicians associated with transplant centers have access to commercially available CAR T-cell products, and community-based research centers are preparing to engage in clinical trials of CAR T-cell protocols in which the toxicity profiles are appropriate to an outpatient setting. The use of CAR T-cell therapies is ushering in a new era of cancer treatment, offering hope to people who had exhausted all other treatment options.

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14. Food and Drug Administration (FDA). Biologics license application approval letter for tisagenlecleucel. https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapy Products/ApprovedProducts/UCM574106.pdf. Published August 30, 2017. Accessed September 26, 2018.  

15. Food and Drug Administration (FDA). Biologics license application approval letter for axicabtagene ciloleucel. https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM581259.pdf. Published October 18, 2017. Accessed September 26, 2018.  

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23 Vineti. www.vineti.com. Accessed September 26, 2018.

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