B-cell aplasia CD19, the cell surface marker that directs CTL019 cells to target tumor cells, is also present on normal, nonmalignant B cells. As a result, CTL019 therapy targets and destroys these normal B cells as well as the leukemic cells, causing B-cell aplasia.36 Other researchers have also reported an association between CD19 CAR T-cell persistence and B-cell aplasia in patients with ALL, DLBCL, and CLL.16,19,23,27

In the most recent analysis of CTL019 in patients with r/r ALL, no serious infections or complications were observed as a result of B-cell aplasia12; however, because B cells produce antibodies, patients who undergo CTL019 therapy often require intravenous immunoglobulin (IVIG) replacement therapy, with administration based on local guidelines. During the consent process for CTL019, patients are made aware they might require IVIG infusions due to B-cell aplasia. IVIG infusions are usually administered in the outpatient setting by an infusion nurse. The side effects are reviewed with the patient prior to IVIG therapy. Patients know to immediately report any symptoms of infection to their physician and to have their immunoglobulin levels routinely checked. In clinical trials in which CAR T-cells persist for a shorter duration, concomitant B-cell aplasia is less of a concern; however, long-term B-cell aplasia may be associated with long-term tumor surveillance.


Continue Reading

THE POTENTIAL OF CTL019 AND CAR T-CELL THERAPY

Although CAR T-cell therapy is not without the potential for serious adverse events, the response rates achieved in patients who had exhausted most other therapies are encouraging, and not often seen in these patient populations. As CAR T-cell therapies continue to be studied, treatment protocols will improve, as will the CAR technology itself. Follow-up remains relatively short and number of patients treated is limited, but the potency of CAR T-cell therapy suggests this treatment strategy will become an important consideration in the management of patients with r/r B cell malignancies.

Acknowledgements

Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. The authors thank Matthew Hoelzle, PhD, for his assistance with this manuscript. They also thank Dr David Porter, MD, and Heather DiFilippo, MSN, CRNP from the University of Pennsylvania for their assistance.

REFERENCES

1. Schreiber RN, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331(6024):1565-1570.

2. Lu B, Finn OJ. T-cell death and cancer immune tolerance. Cell Death Differ. 2008;15(1):70-79.

3. Duttagupta PA, Boesteanu AC, Katsikis PD. Costimulation signals for memory CD8+ T cells during viral infections. Crit Rev Immunol. 2009;29(6):469-486.

4. Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A. 1989;86(24):10024-10028.

5. Eshhar Z, Waks T, Gross G, Schindler DG. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci U S A. 1993;90(2):720-724.

6. Kalos M, Levine BL, Porter DL, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011;3(95):95ra73.

7. Scheuermann RH, Racila E. CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy. Leuk Lymphoma. 1995;18(5-6):385-397.

8. Kershaw MH, Westwood JA, Slaney CY, Darcy PK. Clinical application of genetically modified T cells in cancer therapy. Clin Transl Immunol. 2014;3:e16.

9. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725-733.

10. Porter DL, Kalos M, Zheng Z, Levine B, June C. Chimeric antigen receptor therapy for B-cell malignancies. J Cancer. 2011;2:331-332.

11. Davenport A, Tolwani A. Citrate anticoagulation for continuous renal replacement therapy (CRRT) in patients with acute kidney injury admitted to the intensive care unit. NDT Plus. 2009;2(6):439-447.

12. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507-1517.

13. Grupp S, Maude S, Shaw P, et al. T cells engineered with a chimeric antigen receptor (CAR) targeting CD19 (CTL019) have long term persistence and induce durable remissions in children with relapsed, refractory ALL. Blood. 2014;124(21):Abstract 380.

14. Grupp SA, Maude SL, Shaw PA, et al. Durable remissions in children with relapsed/refractory ALL treated with T cells engineered with a CD19-targeted chimeric antigen receptor (CTL019). Blood. 2015;126(23):Abstract 681.

15. Park J, Riviere I, Wang X, 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(21):Abstract 382.

16. Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2014;385(9967):517-528.

17. Porter D, Frey N, Melenhorst J, et al. Randomized, phase II dose optimization study of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed, refractory CLL. Blood. 2014;124(21):Abstract 1982.

18. Brentjens RJ, Rivière I, Park JH, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood. 2011;118(18):4817-4828.

19. Park JH, Rivière I, Wang X, et al. Impact of the conditioning chemotherapy on outcomes in adoptive T cell therapy: results from a phase I clinical trial of autologous CD19-targeted T cells for patients with relapsed CLL. Blood. 2012;120(21):Abstract 1797.

20. Porter DL, Hwang WT, Frey NV, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7(303):303ra139.

21. Schuster SJ, Svoboda J, 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. J Clin Oncol. 2015;33(suppl):Abstract 8516.

22. Kochendoerfer J, 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):Abstract 550.

23. 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. 2014;33(6):540-549.

24. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188-195.

25. Curran K, Riviere I, Kobos R, et al. Chimeric antigen receptor (CAR) T cells targeting the CD19 antigen for the treatment of pediatric relapsed B cell ALL. Blood. 2014;124(21):Abstract 3716.

26. Turtle C, Sommermeyer D, Berger C, et al. Therapy of B cell malignancies with CD19-specific chimeric antigen receptor-modified T cells of defined subset composition. Blood. 2014;124(21):Abstract 384.

27. Gardner R, Park J, Kelly-Spratt K, et al. T cell products of defined CD4:CD8 composition and prescribed levels of CD19CAR/egfrt transgene expression mediate regression of acute lymphoblastic leukemia in the setting of post-allohsct relapse. Blood. 2014;124(21):Abstract 3711.

28. Porter DL, Lacey SF, Hwang W, et al. Cytokine release syndrome (CRS) after chimeric antigen receptor (CAR) T cell therapy for relapsed/refractory (R/R) CLL. Blood. 2014;124(21):Abstract 1983.

29. Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368(16):1509-1518.

30. Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014;6(224):224ra25.

31. Frey NV, Levine B, Lacey SF, et al. Refractory cytokine release syndrome in recipients of chimeric antigen receptor (CAR) T cells. Blood. 2014;124(21):Abstract 2296.

32. Ravelli A. Macrophage activation syndrome. Curr Opin Rheumatol. 2002;14(5):548-552.

33. Maude SL, Barrett D, Teachey DT, Grupp SA. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 2014;20(2):119-122.

34. Kochenderfer JN, Dudley ME, Carpenter RO, et al. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood. 2013;122(25):4129-4139.

35. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Non-Hodgkin’s lymphomas. Version 2.2016. http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf. Accessed February 25, 2016.

36. June CH, Maus MV, Plesa G, et al. Engineered T cells for cancer therapy. Cancer Immunol Immunother. 2014;63(9):969-975.