When to Refer a Patient for CAR T-Cell Therapy

Introduction

Chimeric antigen receptor (CAR) T-cell immunotherapy is a rapidly emerging and highly publicized new treatment modality, which has gained significant attention for its effectiveness, side effects, and costs. Early-phase clinical trials have shown dramatic results in patients with often heavily pretreated disease, including those with relapsed/refractory childhood acute lymphoblastic leukemia (ALL) and adult diffuse large B-cell lymphomas (DLBCL). With recent US Food and Drug Administration (FDA) approval of two CAR T-cell products in these disease groups and ongoing clinical trials in many other clinical contexts, the number of patients who will receive CAR-based adoptive immunotherapy is expected to grow substantially in the coming years. The criteria by which providers will decide who and when to refer for CAR T-cell therapy will continue to evolve considerably as the field matures, and considerations of referral timing, therapeutic target, and treatment-related toxicity will remain important factors going forward.

In this chapter, we propose a series of questions which the referring provider should consider in deciding when to refer a patient for CAR T-cell therapy. These aim to address key factors in this process including which diseases are appropriate for CAR T therapy, what the expected timelines are for treatment, and what organ function criteria are needed to tolerate therapy. Finally, we will review the use of CAR T-cells in special populations, including elderly and human immunodeficiency virus (HIV)–positive patients, for whom the use of CAR T therapy is less established and will warrant further study as the field continues to grow.

Can My Patient Wait for Chimeric Antigen Receptor T-Cell Therapy?

One of the most significant limitations in access to CAR T-cell therapy is the waiting period needed for product manufacturing. From apheresis to infusion, most CAR T-cell products studied to date have required at least two if not several weeks to complete the necessary procedural steps. For some centers with extensive experience and on-site manufacturing, the process and time requirements may be significantly reduced. However, most institutions considering CAR T-cell therapy for a patient now are either referring a patient to one of these established centers or relying on commercial products that are manufactured at a separate facility and shipped back for the patient's infusion when a sufficient cellular dose has been produced. Numerous attempts have been made to shorten this highly complex and heavily regulated process, including novel cellular processing methods and ongoing efforts to create “off-the-shelf” CAR T-cell products. For now, CAR T-cells remain a therapy requiring significant time investment, which by necessity dictates that only those who are able to wait for treatment are able to receive it.

Knowing that these and other delays may affect the timing of an eventual CAR T-cell infusion, early consideration of potential rate-limiting steps is an important part of a successful referral for CAR T-cell therapy. A few such possibilities include timing of apheresis, additional screening procedures for patients enrolling onto clinical trials, insurance approvals, and coordination of travel to a specialized center.

For some patients, rapidly progressive or CNS-penetrant disease (see below) may require more expedited therapy, either as a temporizing maneuver or instead of CAR T-cells depending on the clinical scenario. Bulky disease has also been postulated as a reason to consider alternative therapies, given that patients with higher disease burden appear to have more pronounced cytokine release following CAR T-cell infusion and may derive less benefit from therapy. Debulking therapy prior to CAR T-cell administration, either in the form of alternative preparative course or via one or more cycles of chemotherapy prior to beginning a dedicated lymphodepletion regimen, may be appropriate on a case-by-case basis. However, this remains an area of active investigation, where no particular strategy in a given context can necessarily be considered standard of care. For patients potentially enrolling onto clinical trials, this is especially important, as different protocols may have varying limitations on prior therapies including bridging or debulking regimens. For now, deciding when to refer patients who may benefit from CAR T-cell therapy but have pressing treatment needs remains a challenge, and providers should weigh the risks of delaying referral carefully against those of earlier intervention with more conventional therapies.

Can My Patient Tolerate the Toxicities From Chimeric Antigen Receptor T-Cell Therapy?

Deciding whether a patient can withstand the unique toxicities of CAR T-cell therapy is another important early consideration in deciding when to refer a patient. These toxicities, which can range from mild to life-threatening, are described in greater detail elsewhere (see Chapter 5, Chapter 6, Chapter 7, Chapter 8 ). It is worth noting that while many efforts are being made to better describe these toxicities and how to manage them when they occur, our ability to accurately predict who will develop life-threatening or fatal CAR-related toxicity remains limited. As such, one general principle when considering any patient for CAR T-cell therapy is whether they could potentially endure the physiologic stress of severe cytokine release syndrome (CRS) or neurotoxicity.

At present, there are no uniformly applied screening criteria for those set to receive CAR T-cell therapy, as compared with allogeneic stem cell transplantation, which requires rigorous screening and published comorbidity assessment scores prior to deciding a patient's candidacy for treatment. Likewise the FDA labels for both tisagenlecleucel and axicabtagene ciloleucel, the two commercially available CAR T-cell products, do not list any absolute contraindications to therapy. However, there are some populations where risk of CRS is thought to be significantly increased. As mentioned, bulky disease appears to correlate with severe CRS and decreased therapeutic efficacy, though CAR T-cells can still be effective in a number of patients with high disease burden. Otherwise eligible patients with poor performance status may be unable to withstand severe CRS and should be considered for other therapies. Patients with an active infection should have their infection adequately treated prior to CAR T-cell infusion. Furthermore, patients who require an external drain for an organ (nephrostomy tube, pleural drain, peritoneal drain, cholecystostomy, etc.) are at high risk of infection and subsequent CRS. Central venous catheters, however, are not considered high risk and are often required for the CAR T-cell infusion.

Most CAR T-cell products are currently prescribed within the context of a clinical trial requiring patients to satisfy screening criteria necessary for trial enrollment. There is currently a gap between this and the necessary screening for patients receiving commercial products. Most clinical trials to date have employed similar restrictions in terms of performance status (usually ECOG 0–1) and cardiopulmonary function. Patients with evidence of heart failure clinically or by cardiac imaging have typically been excluded from trials, as have those requiring supplemental oxygen for any reason. However, other impairments in pulmonary function such as COPD are less consistent, and pulmonary function testing, which is a prerequisite for stem cell transplantation, is not necessarily a requirement at this time.

Further study is still needed in several key groups (see Table 1.1 ), primarily those excluded from the cadre of early-phase clinical trials currently published. Notably the FDA labels for both tisagenlecleucel and axicabtagene ciloleucel caution against use in patients above the age of 65 years; though as mentioned, none of these factors (including age) are currently listed as an absolute contraindication.

When considering patients in one of these categories for CAR T-cell therapy, limiting such referrals to those who are otherwise in good health and ensuring careful communication may help ensure an overall safer outcome in these understudied populations.

Can My Patient Receive Their Care at a Specialized Center?

Though many institutions without prior CAR T-cell clinical trial experience are now treating their first patients with commercially available products, this is for now limited to selected institutions with appropriate training, resources, and monitoring in place. Many of these steps, and much of the posttreatment monitoring that is performed, fall under the Risk Evaluation and Mitigation Strategies (REMS), which are part of the conditional approvals by the FDA for each of the commercial CAR T-cell products.

The goals of these, as listed by the FDA, are the same for each product:

• 1.

  Ensuring that hospitals and their associated clinics that dispense (the CAR T-cell product) are specially certified and have on-site, immediate access to tocilizumab

• 2.

  Ensuring those who prescribe, dispense, or administer (the CAR T-cell product) are aware of how to manage the risks of CRS and neurological toxicities

Similar REMS programs are anticipated for any future CAR T-cell product brought to market, though the exact nature and requirements of such a program may evolve as the field continues to gain experience with CAR T-cell therapy and its complications. It should also be expected that, like other cellular therapies, CAR-T-cell administration will remain restricted to specialized centers for the foreseeable future and that patients will need to remain in close proximity to these centers for at least some prespecified period of time following their initial therapy. Whether a uniform accreditation process for CAR T therapy emerges, through the Foundation for the Accreditation of Cellular Therapy (FACT) or some other organization, remains to be determined. For now, eligibility to administer each commercial product is granted through the pharmaceutical company responsible for the individual product, although FACT accreditation for autologous stem cell transplantation is frequently part of the criteria used in selecting CAR T-cell centers.