Treating patients with CAR T-cell therapy after allogeneic HSCT

Question

What is the evidence for treating patients with CAR T-cell therapy after they have received allogeneic hematopoietic stem cell transplant (HSCT) – is it safe and effective?

Search strategies

Pubmed search using the MeSH terms “chimeric antigen receptor” OR “tisagenlecleucel” OR “axicabtagene ciloleucel” and “allogeneic”

Background

Chimeric antigen receptor (CAR) T-cell therapy is one form of immunotherapy, in which T-cells are removed from a patient, re-engineered, and then re-infused into the patient in order to target a specific malignancy. Through the engineering process, synthetic receptors are engineered onto the T-cell to combine the effector function of the T-cells with the recognition and specificity of an antibody. By engineering these cells, they can function irrespective of the major histocompatibility complex (MHC) system in that they do not require MHC activation, and thus, are not susceptible to MHC escape mechanisms from tumor cells.1

CAR T-cell therapy generally uses lentiviral vectors to deliver RNA into the cells, that are then transcribed and become the cellular receptors. Early CAR T-cell varieties were initially effective, but lacked persistence in the body. Because of this, subsequent generations have been engineered with intramembrane co-stimulators, such as 4-1BB (responsible for the endurance of the cells and inducing T-cell differentiation) and CD3zeta (necessary for T-cell activation). Once the cells are engineered and allowed to proliferate, the patient is treated with an immune depleting regimen or conditioning regimen, and then the cells are re-infused into the patient.2

There are currently two approved CAR T-cell products. The first is tisagenlecleucel (Kymriah®), which targets CD19 and is FDA approved for use in relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and diffuse large B cell lymphoma (DLBCL). The second is axicabtagene ciloleucel (Yescarta®), which also targets CD19 and is approved for use in relapsed/refractory DLBCL, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma. Patients who are to receive treatment with either one of these agents should be free all cytotoxic therapy for at least 2 weeks prior and at least 3 months post-HSCT. Patients should be premedicated with acetaminophen and an antihistamine such as diphenhydramine. Once infused the cells may take approximately 2 weeks to become fully functional.3-5

The biggest safety concerns with CAR T-cell therapy are cytokine release syndrome (CRS) and neurologic toxicity. CRS can range from mild fever to severe hypotension and respiratory distress. Mild-to-moderate manifestations can be observed or treated with supportive care, such as fluids and antipyretics. Severe manifestations require more aggressive management, including the use of corticosteroids, which could potentially blunt the effects of CAR T-cell therapy through immunosuppression, or tocilizumab, an IL-6 receptor antagonist. Neurologic toxicities can manifest as headache, encephalopathy, delirium, and anxiety. Symptoms are typically self-limiting but persistent symptoms can be responsive to steroids.3-6

In the case of patients who have previously received allogeneic HSCT but who are now relapsed, several questions about the utilization of CAR T-cell therapy arise. Should CAR T-cell products be derived from the HSCT donor or the recipient? Are these patients at higher risk for complications such as CRS or HSCT-complications such as graft versus host disease (GVHD)?

Literature Review

One study evaluated 30 adult and pediatric patients with ALL receiving CAR T-cell therapy, 8 of which had underdone HSCT. Overall 90% of patients demonstrated a complete response at 1 month, and event-free survival and overall survival did not significantly differ between patients who had previously undergone HSCT and those who had not.7 Two additional studies, found similar outcomes, with no differences in response rates based on prior HSCT. All three of these studies utilized recipient-derived cells.8,9

Another study evaluated 20 patients with B cell malignancies, who had previously received HSCT and were treated with donor-derived CAR T-cell therapy. They found complete response rates of 30%. This study had much lower response rates than the previous studies, but this study also did not utilize any immune depletion therapy as part of their protocol and all patients had measurable disease at the time of treatment, with 2 patients demonstrating relapse and 12 patients demonstrating progressive disease prior to therapy.10

To further answer the question of cell source for CAR T-cell therapy, one study abstract compared autologous, recipient-derived allogeneic, and donor-derived allogeneic CAR T. Complete response rates were similar between all three groups and there was no difference in overall-survival or event-free survival. Donor-derived allogeneic CAR T recipients had numerically lower rates of complete response, but this was likely due to the small sample size, which only included 3 patients.11

To answer the question of safety, there are a few important considerations. The first is GVHD, which is itself a major safety concern in the allogeneic HSCT population. A retrospective review evaluated 86 patients who had previously been treated with CAR T-cell therapy. Of these 86 patients, 15 of them had previously developed GVHD with their stem cell transplant. Three patients developed GVHD after receipt of CAR T-cell therapy. These 3 patients developed GVHD at 2.8 months, 3.2 months, and 2 months after receiving CAR T-cell therapy and all required treatment with steroids or “multiple lines of therapy,” which was not defined by the authors. Importantly, all of these patients experienced resolution of their GVHD and all three of these patients demonstrated a complete response to CAR T-cell therapy. Although this is a small, retrospective study, it can provide some level of confidence that patients who previously experienced GVHD with their HSCT can still tolerate CAR T-cell therapy. This study also demonstrated that patients who developed GVHD after CAR T-cell therapy and required treatment with corticosteroids and other immunosuppressants, they were not precluded from from reaping the benefits of therapy. 12 Even with this evidence, it is still prudent to avoid corticosteroids and other systemic immunosuppressants if safely possible due to the possibility of interactions with CAR T-cell therapy.

Two additional side effects that are of concern after CAR T-cell therapy are CRS and neurologic toxicities. Rates of CRS seen in efficacy trials ranged from 85-100% of patients. Patients within these studies that experienced CRS received both steroids and tocilizumab for management and receipt of these therapies did not affect response rates or durability of remissions. 7-9 Rates of neurologic toxicities in this patient population ranges from 43-49% with studies reporting patients did not require any interventions for symptoms resolution.7-8

Conclusion

As presented in the evidence above, patients who have previously received allogeneic HSCT and subsequently experience a relapse can safely receive CAR T-cell therapy and derive disease benefit from the therapy, regardless of T-cell source. Although CAR T-cell therapy is associated with important toxicities, patients who have previously received an allogeneic HSCT do not experience these side effects at greater rates than patients who have not.

References

  1. Feins S, et al. Hematology. 2019;94(1):S3-S9.

  2. Vairy S, et al. Drug Des Devel Ther. 2018;12:3885–3898.

  3. Yescarta (axicabtagene ciloleucel) [prescribing information]. Santa Monica, CA: Kite Pharma, Inc; May 2019.

  4. Kymriah (tisagenlecleucel) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; May 2018.

  5. Vairy S, et al. Drug Des Devel Ther. 2018;12:3885–3898.

  6. Hunter BD, et al. J Natl Cancer Inst. 2019 Feb 11.

  7. Maude SL, et al. NEJM. 2014; 371:1507-1517

  8. Gardner RA, et al. Blood. 2017;129(25): 3322-3331

  9. Park JH, et al. NEJM. 2018;378:449-459.

  10. Brudno JN, et al. J clin oncol. 2016;34(10):1112-1121

  11. Hu Y, et al. Blood. 2018;132(supplement 1):2691

  12. Cordeiro A, et al. Biol Blood Marrow Transplant. 2019; 1-8.


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