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Chimeric Antigen Receptor T-Cell Therapies: A Step Closer to Achieving the Magic Bullet in Cancer Treatment

Katie S. Gatwood, PharmD BCOP
Stem Cell Transplant Clinical Pharmacist
Vanderbilt University Medical Center
Nashville, TN


August marked a historic milestone for both the oncology and medical communities with the first U.S. Food and Drug Administration (FDA) approval for a gene therapy, tisagenlecleucel (Kymriah).1 Tisagenlecleucel is the first FDA-approved chimeric antigen receptor T-cell (CAR-T) therapy and has pioneered a new class of “living drugs” in the armamentarium of anticancer therapy. CAR-T cells are T-cells that have been engineered to express antigen-specific receptors and are paired with a costimulatory domain that signals activation of the cell.2 CAR-T construct design has already undergone significant progress in the short time since the therapy’s inception, making possible improvements in both efficacy and safety.2 First-generation CAR-T cells possessed a ligand-derived extracellular domain and only a single signaling domain, making persistence of the cells a major limitation. The third- and fourth-generation CAR-T cells currently being tested in clinical trials have more sophisticated antibody-derived extracellular domains and three or four signaling domains.2 Thus far, the therapy has been most heavily studied in B-cell malignancies because, until recently, CAR-T cells could target only extracellular antigens and B-cells express well-established cell surface markers.2 Additionally, CAR-T cells can easily access the site of disease in B-cell malignancies because these cells are disseminated in areas of the body where T-cells naturally circulate, such as the bloodstream.2 The early but encouraging results of CAR-T cells in this setting have served as proof of concept for the therapy and incited rapid investigation of its application in a wider variety of cancers.

CD19 has been the most common target for CAR-T therapies developed to date and has been extensively tested in clinical trials. Tisagenlecleucel is a CD19-directed CAR-T product, and its breakthrough therapy approval comes after several years of investigation in relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). The most recent data from the multicenter phase-2 ELIANA trial were presented at the European Hematology Association (EHA) Annual Congress in June 2017. The investigators reported that of the 63 pediatric and young adult patients in the trial evaluable for the primary end point, 83% (95% confidence internal [CI]: 71%–91%) achieved a complete remission (CR) or complete remission with incomplete blood count recovery within 3 months of infusion, with no detection of minimal residual disease at a median follow-up of 6.4 months, which may be suggestive of durability of response.3 Among responders, there was a 12-month relapse-free probability of 64% (95% CI: 42%–79%) and 12-month survival probability of 79% (95% CI: 63%–89%).3

Several other trials conducted in adult and pediatric patients with relapsed or refractory ALL have reported results similar to those of the ELIANA trial, with complete remissions ranging from 70% to 91%.4-6 One of these studies also demonstrated persistence of the CAR-T cells with sustained remissions and associated B-cell aplasia for up to 2 years following infusion without further therapy.5 CAR-T therapy has also been shown to be effective in patients who are refractory to the bispecific T-cell engager blinatumomab.5 In one trial, 3 of the 30 total patients had prior exposure to blinatumomab, and 2 of these patients were able to achieve a CR with CD19 CAR-T therapy. However, one of these patients eventually relapsed with CD19-negative disease.5 The authors felt that these results suggest that lack of response to prior CD19-directed therapy does not preclude success with CD19 CAR-T cell treatment. However, it should be noted that all patients included in this trial still had CD19-positive disease at enrollment.5

In other relapsed or refractory B-cell malignancies, CD19-directed CAR-T therapy has demonstrated mixed responses. A small number of patients (22%–50%) have achieved complete responses in CD19 CAR-T cell trials in chronic lymphocytic leukemia, mantle cell lymphoma, and follicular lymphoma, with a greater proportion of patients in these studies achieving only partial responses (PR) or stable disease.7-8 Positive results have also been observed in diffuse large B-cell lymphoma (DLBCL), where CAR-T therapy has demonstrated CR rates of 50% or higher with some durable remissions.9-11 Data from the interim analysis of the multicenter phase-2 JULIET trial were also presented at this year’s EHA Congress. Of the 85 patients included in the trial, 51 patients with multiply relapsed DLBCL were evaluable, and a CR rate of 37% and a PR rate of 8% at a median of 3.7 months postinfusion have been reported.10 Relapse-free survival at 6 months was 79%, and all patients who achieved a CR at 3 months maintained it until the time of data cutoff for the analysis.10 The phase-2 ZUMA-1 trial has also shown positive results in DLBCL, with a CR of 39% at a median follow-up of 8.7 months among the 72 patients treated.11 This trial was also notable in its improvement in manufacturing time for the CAR-T cells, with an average of 17 days between apheresis and return shipment from the manufacturer, which compares to a more typical average time of 28 days in previous CAR-T cell studies.11 Initial investigations of the application of CAR-T therapy in multiple myeloma (MM) have also used CD19-directed CAR-T, with one case series of 10 patients reporting achievement of a PR or very good partial response (VGPR) in 3 patients who remained free from progression at last follow-up (range 70–222 days). An additional 3 patients in the study were also progression-free, but not yet evaluable for response.12 The utility of CD19 CAR-T in MM remains to be determined, and additional studies are ongoing.

Cytokine release syndrome (CRS) and neurologic toxicity are the most well documented serious adverse events associated with CAR-T cell therapy and occur during in vivo cell expansion. CRS is characterized by fevers, hypotension, and other reversible associated toxicities, such as neurologic disturbances and respiratory dysfunction, and can be life-threatening.13 However, it has been noted that the occurrence, but not the severity, of CRS is correlated with response rates.4 Close monitoring, careful management, and use of anticytokine therapy have been used to control these toxicities and maintain both safety and efficacy.2 Tocilizumab, an interleukin-6 receptor antagonist, is most frequently used for management of grade 3–4 CRS and received FDA approval for this indication with the approval of tisagenlecleucel.1 It may be necessary for patients to receive multiple doses of tocilizumab for the treatment of CRS; however, if CRS is unresponsive to tocilizumab, steroids (dexamethasone or methylprednisolone) are typically initiated.14 Other agents that have been used in the second-line treatment of CRS include etanercept and siltuximab, but these have typically been used only in the setting of clinical trials because CRS can usually be effectively managed with tocilizumab and corticosteroids.14 Recent clinical trials of certain CAR-T constructs have also begun to incorporate administration of a prophylactic dose of tocilizumab 36 hours following CAR-T cell infusion in an effort to reduce the severity of CRS. Preliminary results from one of these trials reported a grade 3 or higher CRS incidence of 13%, compared to the incidence in previous trials ranging from 27% to 53%.11,13 In addition, other strategies related to cell dose, fractionated administration, thresholds for tumor burden at time of infusion, and incorporation of suicide genes or protein co-expression that can be targeted by commercial depleting antibodies continue to be tested in clinical trials in an effort to identify the safest mode of administration of this therapy.2

Other major limitations of CAR-T cells are lack of persistence in some patients, tumor evasion, and resistance. Despite the promising results of initial CD19 CAR-T trials, a subset of treated patients have relapsed with CD19-negative disease or with CD19-positive disease when CAR-T cell levels become undetectable.2 Strategies currently in clinical testing to overcome resistance include dual antigen targeting (e.g., CD19 and CD123) or antigen and chemokine co-expression, use of CAR-T cells engineered to no longer express immune checkpoint molecules such as programmed cell death protein/ligand 1 (PD1/PDL1), and the co-administration of CAR-T therapy and PD1 monoclonal antibodies.2 CAR-T cell persistence is highly variable, according to the target antigen, the costimulatory domain, and cell culture systems and manufacturing processes used.2 CAR-T cell persistence is not the only correlate of durable efficacy, and optimal persistence duration remains an area of active investigation; novel constructs are continuing to be developed to improve this aspect of the therapy.2,13

CAR-T target selection has quickly evolved into the proverbial space race of cancer immunotherapy. Current targets under investigation in hematologic malignancies include CD20, CD22, and CD30 for B-cell malignancies; CD33 and CD123 for myeloid malignancies; and CD138, immunoglobulin-κ light chains, and B-cell maturation antigen (BCMA) for MM in hopes of improving both efficacy and disease specificity.2,13 Encouraging preliminary data of BCMA-directed CAR-T in MM was recently reported, with 33 out of 35 relapsed or refractory patients enrolled in a phase-1 trial demonstrating a clinical remission (CR or VGPR) within 2 months of infusion.15 Furthermore, 19 of these patients have been followed for more than 4 months, 14 of which have achieved a stringent CR (sCR) without a single case of relapse.15 Five of these patients have been followed for more than 1 year and remain in sCR and free of minimal residual disease.15 CAR-T therapy is also beginning to penetrate the world of solid tumors; clinical trials are either currently under way or planned using the following targets: human epidermal growth factor receptor 2 in sarcoma and glioblastoma multiforme, interleukin 13 receptor-α in glioma, disialoganglioside GD2 in neuroblastoma, and carcinoembryonic antigen in lung, breast, colorectal, and gastric cancers.2,13 Solid tumor application of CAR-T cells will pose unique challenges because these targets are often not expressed uniformly on tumor cells as they are in hematologic malignancies and will likely result in further enhancements in the engineering of this therapy.2

A discussion of CAR-T therapy without mention of cost would unfortunately be incomplete. Cost has emerged as a primary concern with the approval of tisagenlecleucel and its associated $475,000 price tag.16 The product’s manufacturer, Novartis, has struck a first-of-its-kind pay-for-performance deal with the Centers for Medicare and Medicaid Services that will fully reimburse the cost of therapy in the event that no response is seen by 1 month after infusion; however, questions and debates regarding reimbursement and pricing still abound.17 The manufacturer is also providing copay and travel assistance programs, given that the therapy will not be immediately available at all centers.17 Regulation and practical administration for CAR-T therapy is also uncharted territory because, despite being an engineered human cell product, it is being regulated by the FDA as a drug. This situation will likely create novel challenges for pharmacy departments, with unique considerations related to product labeling and dispensing, budgeting, risk evaluation and mitigation strategies (REMS) program management, and reimbursement. Little guidance is available on these issues, though many institutions are currently navigating their way through them and may be able to share their experiences in the future. The Foundation for the Accreditation of Cellular Therapy (FACT) has created the first set of accreditation standards for programs administering immune effector cell therapy; they provide guidelines and minimum requirements for appropriate management of these therapies from an institutional perspective and are an excellent resource for institutions that will provide this therapy.18 Creation of standard operating procedures for monitoring and management of toxicities and educational and training requirements of key personnel, including pharmacists, are among the outlined requirements set forth by FACT, and these, when complete, will fulfill the majority of requirements of the tisagenlecleucel REMS program.18 We are seeing just the tip of the iceberg of CAR-T therapy, and as the technology improves and is used more widely, further questions and challenges will undoubtedly arise. However, for the present, we should all revel in this unique and exciting breakthrough in the war against cancer and all the potential it holds.  

References

  1. U. S. Food and Drug Administration. FDA approval brings first gene therapy to the United States [news release]. August 30, 2017. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm
  2. Fesnak AD, Levine BL, June CH. Engineered T cells: the promise and challenges of cancer immunotherapy. Nat Rev Cancer. 2016;16(9):566-581.
  3. Buechner J, Grupp SA, Maude SL, et al. Global registration trial of efficacy and safety of CTL019 in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia: update to the interim analysis. Paper presented at 22nd Congress of the European Hematology Association; June 22-25, 2017; Madrid, Spain. Abstract S476.
  4. Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukemia in children and young adults: a phase I dose-escalation trial. Lancet. 2015;385:517-528.
  5. Maude SL, Frey N, Shaw PA, et al. Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia. New Engl J Med. 2014;371:1507-1517.
  6. Park JH, Riviere I, Xiuyan W, et al. CD19-Targeted 19-28z CAR-Modified Autologous T Cells Induce High Rates of Complete Remission and Durable Responses in Adult Patients with Relapsed, Refractory B-Cell ALL. Blood. 2014;124:382.
  7. Kochenderfer JN, Somerville R, Lu L, et al. Anti-CD19 CAR T cells administered after low-dose chemotherapy can induce remissions of chemotherapy-refractory diffuse large B-cell lymphoma. Blood. 2014;124(21):550.
  8. Schuster SJ, Svoboda J, Dwivedy Nasta S, et al. Phase IIa trial of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas. Blood. 2015;126(23):183.
  9. Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T-cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015;33:540-549.
  10. Schuster SL, Bishop MR, Tam C, et al. Global pivotal phase 2 trial of the CD19-targeted therapy CTL019 in adult patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL)—an interim analysis. Paper presented at 22nd Congress of the European Hematology Association; June 22-25, 2017; Madrid, Spain. Abstract LB2604.
  11. Locke FL, Neelapu SS, Bartlett NL, et al. Clinical and biological covariates of outcomes in ZUMA-1: A pivotal trial of axicabtagene ciloleucel (AXI-CEL; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL). Paper presented at 22nd Congress of the European Hematology Association; June 22-25, 2017; Madrid, Spain. Abstract S466.
  12. Garfall AL, Maus MV, Hwang WT, et al. Chimeric antigen receptor T cells against CD19 for multiple myeloma. N Engl J Med. 2015;373:1040-1047.
  13. Jackson HJ, Rafiq S, Brentjens RJ. Driving CAR T-cells forward. Nat Rev Clin Oncol. 2016;13(6):370-383.
  14. Lee DW, Gardner R, Porter DL, et al. Clinical concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188-195.
  15. Fan FX, Zhao W, Liu J, et al. Durable remissions with BCMA-specific chimeric antigen receptor (CAR)-modified T cells in patients with refractory/relapsed multiple myeloma. J Clin Oncol. 2017;35(18). doi:10.1200/JCO.2017.35.18_suppl.LBA3001 [Epub ahead of print].
  16. Rosenbaum L. Tragedy, perseverance, and chance—the story of CAR-T therapy. N Engl J Med. 2017 Sep 13. doi: 10.1056/NEJMp1711886 [Epub ahead of print].
  17. Mukherjee, S. The way we treat cancer will be revolutionized as gene therapy comes to the U.S. Fortune. 2017(Aug 30). http://fortune.com/2017/08/30/fda-novartis-car-t-kymriah/
  18. Foundation for the Accreditation of Cellular Therapy. Immune Effector Cell Standards. www.factwebsite.org/iecstandards/
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