by Dr. C.H. Weaver M.D. updated 6/2021

The US Food and Drug Administration (FDA) has approved several chimeric antigen receptor (CAR) technologies for the treatment of malignant lymphoma. The different agents utilize slightly different methods of genetic engineering to transform the patient’s T cells into CAR-T cells. However all agents produce CAR T cells that bind to the CD19 protein; an antigen found on the surface of B- cells.

  • Kymriah™ (tisagenlecleucel), is for the treatment of children and young adults up to the age of 25 years with B-cell precursor acute lymphoblastic leukemia (ALL). ALL is the most common cancer, as well as the most common cause of cancer-related deaths, among children in the United States.
  • Yescarta™ (axicabtagene ciloleucel) is approved for the treatment of adults with diffuse large B-cell lymphoma (DLBCL) and was granted accelerated approval for the treatment of adult patients with relapsed or refractory follicular lymphoma in Feb 2021.
  • Tecartus™ (brexucabtagene autoleucel, formerly KTE-X19) was approved in July 2020 for the treatment of advanced Mantle Cell Lymphoma
  • Breyanzi (lisocabtagene maraleucel) On February 5, 2021, the Food and Drug Administration approved Breyanzi - a CD19 CAR T cell directed therapy (lisocabtagene maraleucel) for the treatment of adult patients with relapsed or refractory large B-cell lymphomas.

Second-generation CAR T cellular immunotherapy products are being developed to overcome resistance, reduce side effects and simplify treatment. Both allogenic umbilical cord blood derived CAR T cells and FT596 appear very promising.

CAR therapies utilize T-cells (CART T), a patient’s own immune cells that are re-programmed to recognize and kill cancer cells throughout the body. The process involves the removal of some T cells from a patient, and through laboratory processes, these T cells are re-programmed to identify a patient’s cancer cells.

Once the T cells have been programmed to identify a patient’s cancer cells, they are replicated in the laboratory, and infused back into the patient. These re-programmed T cells circulate throughout the body, identifying the cancer cells and mounting an immune attack against them. Simultaneously, the T cells are replicating within the body, so that more of the immune cells can identify and attack the cancer cells.

Learn More About CAR T Therapy Here

Recurrent Large B Cell Lymphoma

The current standard of care for recurrent large B cell or other intermediate or high grade lymphomas is autologous stem cell transplant (ASCT). Early studies suggested CAR T cell therapy produced equivalent outcomes and a recent report suggests Breyanzi may be superior to ASCT. When considering CAR T or ASCT patients need to understand the acute side effects, long term consequences of treatment, and overall cost of therapy.  

ZUMA-1 Recurrent Large B Cell Lymphoma

The ZUMA-1 clinical trial enrolled 111 adults with relapsed or refractory large B-cell lymphoma to receive treatment with a chemotherapy regimen of fludarabine and cyclophosphamide followed by a single infusion of Yescarta.

In the ZUMA-1 clinical trial, Yescarta showed durable responses.  Of 111 patients enrolled in the ZUMA-1 Phase 2 cohorts, Yescarta was administered to 101 patients with refractory LBCL, and the median time from leukapheresis to complete response (CR) was less than two months. There have been no Yescarta-related secondary malignancies reported and the four-year overall survival rate was 44%.2,5,16

Overall 83% of treated patients responded to treatment and 58% had a complete response. With a minimum follow-up of three years after a single infusion of Yescarta (median follow-up of 39.1 months), 47% of patients with refractory large B-cell lymphoma in the ZUMA-1 clinical survive, and the median overall survival was 25.8 months.

Tecartus (KTE - C19) Kite Pharma reported on 51 patients with advanced diffuse large B-cell lymphoma (DLBCL) who were treated with Kite’s KTE-C19. Initially, 76% of the patients responded to treatment, 47% of patients went into complete remission. Two lymphoma patients in the study died due to treatment with KTE-C19. Serious neurological toxicity was reported in 34% of patients. Another trial evaluating the effectiveness of CAR T cell therapy included 22 patients with different types of advanced B-cell lymphomas that had progressed following prior therapies. All patients received chemotherapy prior to a single infusion of the CAR T cells.14

CAR T as Initial Therapy for Aggressive NHL

Yescarta appeared effective and well tolerated as initial therapy for high-risk large B-cell lymphoma in the phase 2 ZUMA-12 clinical trial. Initial data was presented at the December 2020 American Society of Hematology annual meeting. ZUMA-12 is the first study to evaluate CAR T-cell therapy as the initial therapy for high-risk large B-cell lymphomas and comparative trials will be necessary in order to determine if CAR T cell therapy improves health outcomes compared to current standards of care.17

Follicular and Marginal Zone Lymphomas

CAR T cell therapy is FDA approved for the treatment of refractory Follicular and Marginal Zone lymphomas. In theZUMA-5 clinical trial Yescarta CAR T cell therapy was administered to 146 patients with follicular or marginal zone lymphoma. Despite undergoing multiple previous treatments 91% of patients with relapsed or refractory FL responded to Yescarta and 74% of patients remained in continued remission at 18 months.15,18

Results from the phase II ELARA CAR T cell trial of Kymriah® (tisagenlecleucel) in patients with relapsed or refractory follicular were updated at the 2021 Annual American Society of Clinical Oncology (ASCO) Virtual Scientific Meeting.

The ELARA clinical trial was designed to evaluate Kymriah in adult patients with relapsed FL and was performed in 97 patients from over 30 sites in 12 countries worldwide. At the time of reporting 94 patients were evaluable with a median follow-up of 11 months. Kymriah led to responses for the majority of patients treated - 86% of patients responded and 66% achieved a complete response. The duration of response to Kymriah has not been reached.

Patients did experience well documented side effects of CAR T cell therapies including prolonged low blood cell counts and hypogammaglobulinemia, a condition in which the level of immunoglobulins (antibodies) in the blood is low and the risk of infection is increased. It is expected that patients may develop hypogammaglobulinemia with Kymriah and may need to receive immunoglobulin replacement for an indefinite amount of time following treatment with Kymriah.18

Mantle Cell Lymphoma

The US FDA granted accelerated approval to Tecartus for the treatment of relapsed or refractory Mantle Cell Lymphoma (MCL) based on the ZUMA-2 clinical trial in which 62% of patients achieved a complete remission to a single treatment.10,14

Findings for the first 60 treated patients with a median follow-up of 12.3 months were reported at ASH 2019 -  One-year overall survival was 83% and cytokine release syndrome (CRS) occurred in 91% of individuals a median of two days after KTE-X19 administration – all resolved.

CAR T cell therapy appears to be a promising new treatment option for individuals with relapsed or recurrent MCL which led to the FDA approval for Mantle Cell lymphoma.

Breyanzi (lisocabtagene maraleucel) On February 5, 2021, the Food and Drug Administration approved Breyanzi (lisocabtagene maraleucel) for the treatment of adult patients with relapsed or refractory large B-cell lymphomas.

The TRANSCEND clinical trial evaluated Brevanzi preceded by lymphodepleting chemotherapy, in adults with recurrent large B-cell lymphoma after at least two lines of previous therapy. Of the 192 patients evaluable for response, the overall response rate was 73% with a complete response rate of 54%. Of the 104 patients who achieved CR, 65% had remission lasting at least 6 months and 62% had remission lasting at least 9 months. The estimated median duration of response has not been reached at the time of the approval. The estimated median duration of response among patients with partial response was only 1.4 months.

Side Effects of CAR T Cell Therapy

The most common side effects with CAR T Cell therapy are  anemia, neutropenia, thrombocytopenia, hypotension, hypophosphatemia, encephalopathy, leukopenia, hypoxia, and fever. Two unique side effects are therapy associated neurotoxicity and cytokine release syndrome (CRS).

  • Cytokine Release Syndrome (CRS): CRS occurs in a majority of patients with a median time to onset of 2-5 days (range: 1-17 days) and a median duration of 7 days (range: 2-58 days). Key manifestations of CRS include fever (78%), hypotension (41%), tachycardia (28%), hypoxia (22%), and chills (20%). At the first sign of CRS physicians now institute treatment with tocilizumab and/or corticosteroids. CRS has been associated with fatality. 
  • Neurologic side effects: Neurologic side effects are reported to occur, occurring within the first 8 weeks of therapy. The most common include encephalopathy (57%), headache (44%), tremor (31%), dizziness (21%), aphasia (18%), delirium (17%), insomnia (9%) and anxiety (9%). Prolonged encephalopathy lasting up to 173 days has been reported.  Serious events including leukoencephalopathy and seizures as well as fatal and serious cases of cerebral edema. Median duration of neurologic toxicity is reported to be 15 days (range: 1 to 785 days).
  • Prolonged Cytopenias" Patients may exhibit cytopenias not resolved for several weeks following lymphodepleting chemotherapy and CAR T infusion.
  • Hypogammaglobulinemia: B-cell aplasia and hypogammaglobulinemia can occur in up to 15% of patients. 
  • Live vaccines: Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy.
  • Secondary Malignancies: Patients treated with CAR T may develop secondary malignancies. 

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While the initial FDA approval is for "transplant ineligible patients" there is of course great hope that CAR T cell therapy will also improve the outcomes compared with stem cell transplant used earlier in the disease course. It is of interest that the treatment related mortality from CAR T of ~ 4% and the 3 year disease free survival are similar to that obtained with a standard stem cell transplant. Moreover the neurologic side effects and CRS are not insignificant. Comparative clinical trials may be necessary to determine how the side effects compare to a standard stem cell transplant and whether the additional cost for CAR-T cell therapy is warranted.

Advances in CD19‐targeted CAR T‐cell therapies have led to a new standard of care for heavily pretreated relapsed/relapsed diffuse large B‐cell lymphoma (DLBCL). Despite the clinical benefits of CAR T‐therapy, only 29% to 37% of patients with relapsed/refractory DLBCL achieved a durable complete response.2,11

Several potential mechanisms of resistance to CD19‐directed CAR T‐cell therapy have been proposed, including CD19 antigen loss and programmed death‐ligand 1 (PD‐L1) upregulation, leading to CAR T‐cell exhaustion. (12,13) Strategies to overcome these resistance mechanisms include the simultaneous targeting of both CD19 and CD22 to reduce the probability of antigen loss, as well as the use of a checkpoint inhibitor to prevent PD‐L1‐mediated CAR T‐cell exhaustion.

New Approaches Aim to Enhance CAR T-Cell Therapy

CAR T cell therapies are developed by collecting a patient’s own T cells and engineering them to target proteins specific to the surface of their cancer cells and reintroducing these modified T cells back into the patient’s immune system to kill the cancer cells. First-generation CAR T-cell therapies primarily target CD-19, a protein found on the surface of most normal and malignant B cells in B cell cancers such as lymphoma. Current CAR T-cell therapies need to become more effective, more affordable and safer. The results of early-phase clinical studies of “second-generation” CAR T cellular immunotherapy products may overcome resistance, reduce side effects and simplify treatment.

CD19 /CD22 Dual‐Targeted CAR‐T Therapy

AUTO3 is an investigational CAR T‐cell therapy targeting both the CD19 and CD22 antigens on lymphoma cells and shows promise when combined with Keytruda (pembrolizumab) immunotherapy in patients with relapsed/refractory diffuse large B‐cell lymphoma (DLBCL), according to results from the Alexander phase I clinical trial released at the 2020 American Society of Clinical Oncology Annual meeting.

AUTO3 delivers two CARs targeting CD19 and CD22, respectively, in a single retroviral vector. The phase I/II Alexander clinical trial was designed to evaluate the safety and effectiveness of AUTO3 in combination with the checkpoint inhibitor Keytruda (pembrolizumab) in patients with relapsed/refractory DLBCL.

A preliminary report on the first 23 patients demonstrated that 65% of patients with relapsed/refractory DLBCL responded to treatment and no cases of severe cytokine release syndrome were observed - one patient developed grade 3 neurotoxicity. The patient was treated with steroids, and symptoms improved in 3 days. These preliminary findings suggest that a dual‐targeted anti‐CD19/CD22 CAR T‐cell therapy is safe and effective for patients with relapsed/refractory DLBCL.9,10

Allogeneic CAR T Cell Therapy

Allogeneic derived chimeric antigen receptor (CAR) cell meaning the cells were taken from a non-related healthy donor rather than the patient themselves may have several advantages including;

  • The potential to be manufactured in advance and stored for off-the-shelf immediate use which is in contrast to most available CAR T cells which require the use of a patient’s own genetically modified T cells, created through a multi-week manufacturing process.
  • Avoidance of CAR T cell cytokine release syndrome and neurotoxicity.
  • Lower cost.

Researchers have used allogenic umbilical cord blood-derived chimeric antigen receptor (CAR) natural killer (NK)-cell therapy targeting CD19 in patients with relapsed or refractory non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL), with no major side effects observed. Eleven patients participating in the study had NK cells isolated from donated umbilical cord blood and genetically engineered to express the CAR, which recognizes CD19. The CAR NK cells were also ‘armored’ with IL-15, an immune signaling molecule that is designed to enhance expansion and survival of the cells.6

Side effects experienced by participants were primarily related to the conditioning chemotherapy given before cell infusion and were resolved within one to two weeks and no patient required admission to an intensive care unit for management of treatment side effects. Seventy-three percent of patients responded to therapy and seven of those achieved a complete response. Responses to the CD19 allogenic CAR NK cell therapy were evident within one month following infusion, and persistence of CAR T cells was confirmed out to one-year post-infusion. Importantly NO patients experienced cytokine release syndrome or neurotoxicity.

Off-the-Shelf CAR NK Products – FT596

Cellular immunotherapy for B cell cancers could ultimately become an off-the-shelf product, capable of being uniformly manufactured in large quantities as prescription drugs are.

A product, dubbed FT596, is among the first cellular immunotherapies to be based on off-the-shelf NK cells – the “first line of defense” of the immune system – and is the first cellular immunotherapy to be genetically engineered to contain three active anti-tumor components

FT596 demonstrated comparable ability to kill cancerous white blood cells as standard CAR T cells and, when combined with the drug Rituxan, killed cancerous white blood cells that were no longer responding to standard CAR T-cell therapy due to loss of the CD19 antigen target.

The U.S. Food and Drug Administration (FDA) approved Fate Therapeutics’ Investigational New Drug Application for FT596 in September 2019 and the first patient was treated in March of 2020.

The process of creating FT596 begins with human induced pluripotent stem cells (iPSCs) that are uniquely capable of unlimited self-renewal and can differentiate into more than 200 types of human cells. The iPSCs are genetically engineered, after which a single clone (genetically engineered cell) is selected and multiplied in the laboratory to create a master engineered cell line that can be repeatedly used to generate cancer-fighting immune-system cells such as NK and T cells.

In addition to engineering FT596 to carry a CAR targeting the CD19 protein – which is produced by nearly all B-cell lymphomas and leukemias researchers inserted two other novel proteins: CD16, which boosts and broadens the NK cells’ ability to kill cancer cells, and IL15, which stimulates FT596 to multiply and survive longer.

FT596 has been designed to address two other limitations of CAR T-cell therapy.

  • As an off-the-shelf product the time-consuming and costly process that is currently required to treat a patient with CAR T cells is eliminated.
  • The addition of the CD16 protein gives FT596 broader therapeutic activity and versatility. In combination with a drug such as Rituxan, FT596 has the potential to lead to deeper and more durable responses and overcome resistance that hampers the long-term efficacy of CAR T-cell therapy.7,8

References:

  1. FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma
  2. Locke FL, Ghobadi A, Jacobson CA, et al. [Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): A single-arm, multicentre, phase 1–2 trial](https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18%2930864-7/fulltext). Lancet Oncol. 2019;20(1):31-42.
  3. Aspartame Not Linked to Brain or Blood Cancer
  4. CAR T Cell Therapy for The Treatment of Cancer
  5. Kite Announces Long-term Data From ZUMA-1 Showing Approximately Half of Refractory Large B-cell Lymphoma Patients Were Alive Three Years After Yescarta Treatment
  6. nejm.org/media/doi/full/10.1056/NEJMoa1910607
  7. FT596
  8. KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma
  9. CD19/CD22 Dual‐Targeted CAR‐T Therapy Active in Relapsed/Refractory DLBCL
  10. Osborne W, Marzolini, Tholouli E et al. Phase I Alexander study of AUTO3, the first CD19/22 dual targeting CAR T cell therapy, with pembrolizumab in patients with relapsed/refractory (r/r) DLBCL. Presented at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program. May 29–31, 2020. Abstract 8001. Available at: ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.8001
  11. Schuster SJ, Bishop MR, Tam CS et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B‐cell lymphoma. N Engl J Med 2019; 380: 45– 56.
  12. Yoon DH, Osborn MJ, Tolar J et al. Incorporation of immune checkpoint blockade into chimeric antigen receptor T cells (CAR‐Ts): Combination or built‐In CAR‐T. Int J Mol Sci 2018; 19: 340.
  13. Neelapu SS, Locke FL, Bartlett NL et al. Axicabtagene ciloleucel CAR T‐cell therapy in refractory large B‐cell lymphoma. N Engl J Med 2017; 377: 2531– 2544.
  14. U.S. FDA Approves Kite’s Tecartus™, the First and Only CAR T Treatment for Relapsed or Refractory Mantle Cell Lymphoma
  15. 700 Primary Analysis of Zuma-5: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory (R/R) Indolent Non-Hodgkin Lymphoma (iNHL)
  16. New Four-Year Data Show Long-Term Survival in Patients With Large B-Cell Lymphoma Treated With Yescarta® in ZUMA-1 Trial
  17. 405 Interim Analysis of ZUMA-12: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) as First-Line Therapy in Patients (Pts) With High-Risk Large B Cell Lymphoma (LBCL)
  18. Schuster, S. et.al. Efficacy and Safety of Tisagenlecleucel in Adult Patients With Relapsed/Refractory Follicular Lymphoma: Primary Analysis of the Phase 2 ELARA Trial. Oral Presentation #7508. 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, June 4-8, Chicago, IL.