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Process and General Management of Patients Undergoing Chimeric Antigen Receptor Therapies
Introduction
The introduction of chimeric antigen receptor (CAR) T-cell therapies represents the culmination of a decades-long journey to harness the immune system and exploit the antitumoral potential of immune cells to treat cancer. The first clinical experiences describing the administration of genetically engineered CD19-directed CAR T-cells (CART19) derived from patients’ own T lymphocytes for B-cell lymphoid neoplasms were published between 2011 and 2013. These pilot and phase 1 studies enrolled few patients and were descriptive in nature, with a focus on their respective treatment schemas. There was heterogeneity between study protocols, evidenced by the lack of a standardized approach to lymphodepleting therapy before CART19 infusion or clinical and laboratory monitoring postinfusion. It were these pioneering studies that paved the way for the explosion of the U.S. Food and Drug Administration (FDA) approvals of autologous CART19 products for the treatment of relapsed or refractory acute lymphoblastic leukemia, large B-cell lymphomas, mantle cell lymphoma, and follicular lymphoma, with numerous ongoing clinical trials. Recently the B-cell maturation antigen-directed idecabtagene vicleucel was the first non-CD19-directed CAR T-cell product approved by the FDA for the treatment of relapsed or refractory multiple myeloma.
The field’s early experiences with CAR T-cell therapy also raised important concerns regarding the specialized infrastructure and standardized protocols needed to support the administration of these novel cellular therapies. There are logistic challenges to delivering a genetically engineered “living product” that requires precise scheduling of necessary interventions, confidence in the chain-of-identity of the product, and particular storage and processing conditions. CAR T-cell therapy is also associated with unique and potentially life-threatening short- and long-term toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) that require special monitoring and specific interventions. Universal access to CAR T-cell products outside of clinical trials similar to that of chemotherapy and biologic agents with simpler administration is impossible because of logistic and safety concerns.
It was these concerns that led to the Foundation for the Accreditation of Cellular Therapy (FACT) and the Joint Accreditation Committee of the International Society of Cellular Therapy and European Society of Blood and Marrow Transplantation (JACIE) to formulate and provide immune effector cell (IEC) standards as to provide guidelines for and accredit cellular therapy programs, most recently updated in 2018. IECs encompass any cellular therapy used to modulate a therapeutic immune response, including CAR T-cells. The FDA separately oversees risk evaluation and mitigation strategies programs to decrease risks of CRS and ICANS associated with the approved CAR T-cell products.
Our experience at MD Anderson Cancer Center includes the formation of the CAR T-cell-therapy-associated TOXicity (CARTOX) working group, which developed recommendations for the screening and monitoring of patients receiving these therapies. Here, we offer practical guidance on the essential aspects of the CAR therapy workflow from confirmation of successful manufacture of a patient’s CAR product to cell infusion based on our experience and published national/international guidelines. These aspects include reassessment of patient eligibility/risk, screening tests, lymphodepleting conditioning, product receipt and processing, product infusion and postinfusion monitoring, as well as the recommended personnel and infrastructure for each step. A schema of this process is depicted in Fig. 9.1 .
Our recommendations will pertain mostly to commercial autologous CAR T-cell therapies manufactured at outside facilities as these currently are the only approved products, but the concepts should be relevant for other IEC products currently in development.
Lymphodepleting Conditioning
Lymphodepleting conditioning chemotherapy has long been hypothesized to foster a favorable environment for adoptively transferred tumor-specific T-cells through various mechanisms: these include elimination of inhibitory regulatory T-cells, promotion of a proliferative cytokine milieu, and depletion of competitive host lymphocytes. Lymphodepletion with a fludarabine and cyclophosphamide-based regimen was associated with greater CAR T-cell expansion and survival and improved survival after CART19 for B-cell acute lymphoblastic leukemia and aggressive B-cell non-Hodgkin lymphomas. In general, the field has settled on fludarabine and cyclophosphamide as the preferred lymphodepleting regimen, though bendamustine is recommended as an alternative regimen.
Rescreening and Patient Checklist
Patient eligibility for CAR T-cell therapy should have been confirmed by a multidisciplinary team before patient consent and apheresis of their autologous T-cells. Note that patients have been treated successfully with standard-of-care commercial products who would have been excluded from the pivotal CART19 clinical trials because of comorbidities or other reasons. It is important to rescreen patients before scheduling lymphodepletion, however. The time to manufacture a patient’s CAR T-cell product and deliver it back to the clinical site after apheresis can range from 2 to 3 weeks to greater than 1 month, depending on a number of factors including specific product type and manufacturing issues. A patient with an aggressive relapsed hematologic malignancy can experience sudden changes in their clinical condition during this waiting period. This can be further compounded by the administration of “bridging therapy” in this window, which is used to temporarily control disease but may cause additional toxicity before lymphodepletion.
Successful manufacture, passing of quality controls, and availability of CAR T-cell product must be confirmed before proceeding with lymphodepleting therapy. Adequate recovery time after any bridging therapy is also recommended, though this is not strictly defined. Patients should be screened for major organ dysfunction that may have been caused by bridging therapy. Active infection should be excluded or treated. Appropriate hematologic indices will depend on the disease type and clinician interpretation, as cytopenias may be related to disease involvement of marrow rather than cytotoxic therapy. Tumor lysis syndrome prophylaxis should also be implemented based on patient and disease-specific factors.
The scheduling of lymphodepletion should be planned in coordination with a social worker and nursing coordinator working closely with the clinical team. Because patients often come from out of town to receive CAR T-cell therapy at a FACT-accredited center and may have received bridging therapy at their local institution, it is important to verify that the patient and their caregiver are able to travel and have secured lodging close to the clinical site based on guidelines for the therapy the patient is receiving. Vascular access with either a port-a-cath or other central venous catheter with multiple lumens should be obtained. A baseline magnetic resonance imaging scan of the brain with and without intravenous contrast or computed tomography (CT) scan should be obtained to exclude central nervous system disease and serve as a comparator if the patient develops ICANS after product infusion. An updated disease assessment with positron emission tomography/CT scan for lymphomas or bone marrow biopsy for leukemias or multiple myeloma should be performed before lymphodepletion, and ideally after bridging therapy. A recommended checklist to review before lymphodepletion is described in Table 9.1 .
Table 9.1
Screening Checklist Before Lymphodepleting Conditioning *
| Patient Aspect | Intervention |
|---|---|
| CAR T-cell product | Confirm product available at clinical site |
| ECOG PS | If > 2, consider optimization or supportive care measures |
| Liver function tests | Identify reversible causes if elevated AST/ALT/bilirubin, adjust doses of lymphodepleting chemotherapy, proceed with caution |
| Creatinine clearance | Identify reversible causes if decreased, adjust doses of lymphodepleting chemotherapy, proceed with caution if CrCl <50 |
| Cardiac function | Baseline electrocardiogram and echocardiogram to confirm no uncontrolled arrhythmias or significantly decreased left ventricular ejection fraction. Consider repeating echocardiogram if bridging therapy contained cardiotoxic chemotherapy |
| Tumor lysis syndrome risk | Start urate lowering agent before lymphodepletion if indicated |
| Active infection | Exclude or adequately treat |
| Logistic | Confirm patient has travel and lodging arranged |
| Vascular access | Place port-a-cath or multilumen central venous catheter |
| CNS imaging | MRI or CT imaging of brain |
| Disease assessment | PET/CT or BMBx |
| Patient chart flag | Notification (such as in allergies section) should be added to patient chart that they are a planned recipient of CAR T-cell therapy to avoid inadvertent administration of corticosteroids by other providers |
ALT , Alanine aminotransferase; AST , aspartate aminotransferase; BMBx , bone marrow biopsy; CAR , chimeric antigen receptor; CNS , central nervous system; CrCl , creatinine clearance; CT , computed tomography; ECOG PS , Eastern Cooperative Oncology Group performance status; MRI , magnetic resonance imaging; PET , positron emission tomography;
* Consider involving consultative services for assistance with management of potential clinical issues.
Scheduling and Clinical Site
Fludarabine and cyclophosphamide are typically administered intravenously daily over 3 days for large B-cell lymphomas based on the Phase 1 Multicenter Study (ZUMA-1) and JULIET protocols and over 4 and 2 days for acute lymphoblastic leukemia based on the ELIANA protocol. Lymphodepletion may not be necessary if the absolute lymphocyte count is less than or equal to 1 x 10 9 /L within a week of planned product infusion. In general, patients should proceed with product infusion 3 days after completion of lymphodepletion. If there is a significant delay (i.e., greater than 2 weeks) before CAR T-cell infusion and the lymphocyte count has recovered, clinicians should consider repeating lymphodepletion before product infusion.
Lymphodepletion can be administered either on the outpatient or inpatient setting depending on the infrastructure of the treating clinical site and patient specific factors. If the clinical site has an outpatient infusion center that can administer daily chemotherapy infusions, a laboratory that can quickly process daily patient blood samples for monitoring, and ease of patient access to evaluation by a clinical team in case of complications, then hospital admission is not required. If the facility does not have these resources or there are concerns about clinical complications such as tumor lysis syndrome or infection that necessitate closer monitoring, then hospital admission through both lymphodepletion and CAR T-cell infusion is recommended.
Product Receipt and Processing
The CAR T-cell product manufacturer or sponsor is responsible for ensuring the product passes quality standards for patient administration and cryopreserving the product. Depending on the product, the manufacturer will either ship the product in advance of scheduled cell infusion or time the product to arrive on day of infusion. The nurse coordinator will schedule and confirm planned shipment of standard of care products. At MD Anderson, our dedicated cellular therapy laboratory is notified by the manufacturer or on-site clinical trial coordinator when to expect the shipment and the supervisor will assign a trained staff member to be available to receive the product. Cryopreserved products are shipped in a liquid nitrogen cryogenic dry shipper.
A staff member receives and signs off on the shipment and verifies documentation. They will open the inner chamber of the dry shipper to quickly inspect the product bag or vials for integrity. If the product was delivered in advance of infusion date, the product is transported to a liquid nitrogen vapor phase storage tank and documented in the inventory. Chain of identity is maintained during the entire process.
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