The Impact of CAR T-Cell Therapy on Hematological Malignancies

Publication
Article
OncologyONCOLOGY Vol 38, Issue 3
Volume 38
Issue 3
Pages: 119-121

Jae Park, MD, discussed the use of CAR T-cell therapy across the hematologic malignancies space.

Jae Park, MD

Chief, Cellular Therapy Service
Attending Physician
Department of Medicine
Memorial Sloan Kettering Cancer Center
New York, NY

Jae Park, MD

Chief, Cellular Therapy Service
Attending Physician
Department of Medicine
Memorial Sloan Kettering Cancer Center
New York, NY

Chimeric antigen receptor (CAR) T-cell therapy is a recent addition to the hematological oncology armamentarium. To create CAR T cells, gene editing renders natural T cells more active and more capable of binding to tumor cells. CRISPR technology allows for more precise gene insertions and several simultaneous modifications in T cells, which enhances their cancer-fighting abilities. In this article, Jae Park, MD, explores recent advances and future directions of CAR T-cell therapy that is being accelerated via evolving gene editing technologies.

Q: How has autologous CAR T-cell therapy transformed care for patients with hematologic malignancies?

Park: Autologous CAR T-cell therapy has had a tremendous impact on treatment of patients with hematologic malignancy.1 In cases of non-Hodgkin lymphoma, there are now several autologous CAR T-cell products approved, all targeting CD19. These products initially were studied in patients who had relapsed disease after chemotherapy and autologous transplant—high-risk patients with few treatment options available. Even in this setting, about half the patients were able to achieve a complete remission, and more remarkably, these patients were able to maintain the remission long term after one-time infusion of CAR T cells.2 With the longer follow-up that we have now, we can comfortably call this a curative therapy. Based on that data, CAR T-cell therapy was subsequently studied in earlier lines in lymphoma, and now at least 2 products are approved in the second-line setting and some are under investigation for the first-line setting.3,4

In multiple myeloma, we have 2 approved products targeting BCMA.5 These BCMA CARs can yield high response rates, reaching more than 80% in patients who have failed at least 3 prior lines of therapy, but the durability of the remissions is not as good as in lymphoma patients.6 Whether CAR T-cell therapy could generate more durable responses in earlier lines of multiple myeloma is currently being investigated in ongoing clinical trials.

Leukemia is the third disease front where CAR T-cell therapy has made a big impact. We have 2 products approved targeting CD19 in acute lymphoblastic leukemia.7,8 These patients are, again, highly refractory and relapsed patients, often after allogeneic bone marrow transplant. CD19-targeted CAR T-cell therapy can attain a high initial response rate and about half the patients are able to maintain the remission long term, again, after a single infusion.9

Q: What are some of the limitations of autologous CAR T-cell therapy?

Park: Despite the huge success of autologous CAR T-cell therapy in hematologic malignancies, there are some limitations. First, there are unique adverse effects associated with CAR T-cell therapy such as cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS).1

CRS was a bigger problem when CAR T-cell therapy was initially used. Now we have learned a great deal about its pathophysiology, high-risk patient populations, management, and prophylactic strategies to minimize severe CRS.

ICANS is most commonly seen with the CD19 CARs in leukemia and lymphoma and is less common in patients with multiple myeloma.3,10,11 ICANS is more challenging to manage because the pathophysiology is not as well understood and treatments have a lower response rate compared with CRS. Steroids remain the mainstay of therapy. Because severe cases of ICANS do not respond promptly to steroids and other managements, the key is to prevent ICANS altogether or keep it at low grades, ie, grade 1 and 2. We and others have studied several prophylactic strategies including the use of the IL-1 inhibitor anakinra to address those issues.12

The second limitation is that these are autologous CAR T cells, meaning the T cells are coming from the patients themselves. That can create challenges in selecting optimal timing for T-cell collection, ie, leukapheresis. Some patients might have just received chemotherapy or are on active immunosuppressants that can negatively impact the number of T cells retrieved, or compromise T-cell potency. In other cases, the disease is progressing so rapidly that patients cannot wait until they get scheduled for leukapheresis and then wait until the T-cell infusion, which can take several weeks.1 This wait time limits which patients are able to get this therapy.

The third limitation is that this treatment is currently being administered in cell therapy specialty centers. Due to the possibility of CRS and ICANS, there are regulatory requirements on how closely these patients need to be monitored, and how close to the treatment center they must stay. That limits patients who do not have a caretaker or the financial means to travel to the centers. As the adverse effect profiles of new CAR products and prophylactic and management strategies improve, we are hoping these regulatory rules will be modified in the near future. We must work on improving access so that more patients can receive these potentially curative and life-prolonging therapies.

Q: How do gene editing techniques, including CRISPR, contribute to the development of CAR T-cell products?

Park: Gene editing techniques such as CRISPR have enabled tremendous progress in the field of CAR T-cell development. CRISPR and other gene editing technologies are being used to knock-in, knock out, and/or knock down genes of interest to test how a combination of such specific gene modifications can improve the antitumor efficacy of CAR T cells.13 Armored CAR T cells are modified to deliver inflammatory cytokines specifically at the tumor upon T-cell activation. With advancement of gene editing technologies, CAR T cells can function as a micropharmacy. Whatever we want the cells to deliver, we can build into them within a certain capacity. In addition, several investigators have used CRISPR and other gene editing technologies to insert a CAR into a T-cell receptor (TCR) locus, creating allogeneic or donor-derived, off-the-shelf T cells, thereby expanding the available cell sources beyond autologous T cells for CAR therapies.14

Q: What advantages do allogeneic or off-the-shelf CAR products provide?

Park: One advantage of the off-the-shelf CAR therapies is their immediate availability. Patients can bypass the leukapheresis and the bridging time from collection to infusion, saving them several weeks of wait time and a number of visits to the clinic and infusion centers as well as reducing the number of chemotherapy cycles that often get delivered while waiting for autologous cell delivery.15 The second advantage is that it will allow treatment of patients who are currently not being considered for autologous CAR T-cell therapies due to recent T-cell suppressive chemotherapy exposure or for those who have an insufficient number of T cells or had prior autologous T-cell manufacturing failures. The third is that the T cells for off-the-shelf CARs come from a healthy donor, which means that the cells could be more active, and we do not need to worry about possible manufacturing failure or out of spec products. Lastly, we hope off-the-shelf CAR T cells will drive down the cost since it requires fewer steps in manufacturing and can be made in mass production, similar to antibodies and antibody-drug conjugates. Hopefully, in the future, reducing the regulatory hurdles and the amount of monitoring that the patient needs will reduce costs as well for both autologous and allogeneic CAR products.

Q: What are some of the challenges and limitations in using off-the-shelf CAR products for cancer treatments, and how can gene editing address some of those challenges?

Park: Ideally, the T cells need to be present long enough to control the disease and eradicate tumor cells completely. But it is not yet clear what the optimal duration of T-cell persistence is, and it may depend on tumor burden, disease types, and CAR designs. Plus, we may not want the CAR T cells to persist forever, especially when they also target normal B cells or myeloid cells, which can then cause permanent immune suppression and potential infectious complications.16 Ideally, we want these immune cells to be there long enough to get rid of all the tumor cells, but once the job is done, be gone. That is the holy grail.

With all these caveats in mind, there is a concern that off-the-shelf T cells may not persist as long as autologous CAR T cells due to potential immune-mediated rejections, and [they] may not clear out the tumor as completely.13 To address these concerns, several investigators are conducting additional genetic editing to make allogeneic T cells less susceptible to host immune-mediated rejections and/or make them more potent to overcome the short persistence.

Q: Please describe the safety concerns associated with using gene editing in humans, and how are researchers working to improve its safety and precision?

Park: Recently, we have heard a lot about secondary T-cell lymphomas that might have been caused due to viral integration into an oncogene site.17 While incidences of these events are extremely rare and the benefit of autologous CAR T cells still outweighs this potential risk, this raises some anxiety. But, with CRISPR-edited CAR, that risk is even lower since we know exactly where the CAR is being inserted. However, when multiple gene edits are made, there is an increased risk of recombination events that can lead to unwanted or unanticipated outcomes. How many edits can we make and what are some of the safety effects of doing it? We need to follow these patients long term, not only for the efficacy perspective, but for the safety as well.

Q: Where do you see the future of gene-edited immune effector cell products for oncology in 5 to 10 years, and what current research is most promising?

Park:The field has progressed tremendously over the last 5 years already. We now have several genetically engineered cellular products approved for several disease indications globally.1 These immune effector cell therapies not only work where all other therapies have failed, they sometimes even cure the patients, which is the ultimate goal of any cancer therapy. In the next 5 or 10 years, we want to cure more patients with cancer and increase access to CAR T-cell therapy.

In order to increase the cure rate, we are moving the autologous CAR T-cell therapies currently being used in later lines of treatment to earlier lines. We have learned and seen that these therapies have the most single-agent antitumor activity and there is no reason to save them until other therapies fail. However, in order to do that, we do need to improve their safety, which is being addressed with better CAR designs.

Next, we are studying additional gene editing to create next-generation CARs that are more potent and overcome the limitation of current CARs. In the next 2 or 3 years, we are going to see many results of these studies being presented, and hopefully they can accelerate our quest to cure cancer once and for all.

Lastly, we will see these immune effector cells being used for nonlymphoid hematologic malignancies such as acute myeloid leukemia (AML) and for solid tumors. Several CAR clinical trials are now ongoing for relapsed AML, and TCR-enhanced therapies as well as the tumor-infiltrating lymphocytes in sarcoma and melanoma are getting very close to being approved. I am very excited for the future of immune effector cell therapies and the potential they [have] to change the landscape of cancer therapies.

  1. Sun D, Shi X, Li S, Wang X, Yang X, Wan M. CAR‑T cell therapy: a breakthrough in traditional cancer treatment strategies (Review). Mol Med Rep. 2024;29(3):47. doi:10.3892/mmr.2024.13171
  2. Cappell KM, Kochenderfer JN. Long-term outcomes following CAR T cell therapy: what we know so far. Nat Rev Clin Oncol. 2023;20(6):359-371. doi:10.1038/s41571-023-00754-1
  3. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2021;386(7):640-654. doi:10.1056/NEJMoa2116133
  4. Neelapu SS, Dickinson M, Munoz J, et al. Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial. Nat Med. 2022;28(4):735-742. doi:10.1038/s41591-022-01731-4
  5. Zhang X, Zhang H, Lan H, Wu J, Xiao Y. CAR-T cell therapy in multiple myeloma: current limitations and potential strategies. Front Immunol. 2023;14:1101495. doi:10.3389/fimmu.2023.1101495
  6. Usmani S, Patel K, Parameswaran H, et al. KarMMa-2 cohort 2a: efficacy and safety of idecabtagene vicleucel in clinical high-risk multiple myeloma patients with early relapse after frontline autologous stem cell transplantation. Presented at: 64th ASH Annual Meeting and Exposition; December 10-13, 2022 New Orleans, LA.
  7. FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. September 7, 2017, Accessed March 11, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisagenlecleucel-b-cell-all-and-tocilizumab-cytokine-release-syndrome
  8. FDA approves brexucabtagene autoleucel for relapsed or refractory B-cell precursor acute lymphoblastic leukemia. October 1, 2021, 2021. Accessed March 11, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-brexucabtagene-autoleucel-relapsed-or-refractory-b-cell-precursor-acute-lymphoblastic
  9. Rives S, Maude SL, Hiramatsu H, et al. Tisagenlecleucel in pediatric and young adult patients (pts) with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL): final analyses from the ELIANA study. HemaSphere. 2022;6:13-14. doi:10.1097/01.Hs9.0000843344.19780.98
  10. Shah BD, Ghobadi A, Oluwole OO, et al. Two-year follow-up of KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in adult patients (Pts) with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) in ZUMA-3. J Clin Oncol. 2022;40(suppl 16):7010. doi:10.1200/JCO.2022.40.16_suppl.7010
  11. Bal S, Kocoglu MH, Nadeem O, et al. Clinical activity of BMS-986393 (CC-95266), a G protein-coupled receptor calss C group 5 member D (GPRC5D)-targeted chimeric antigen receptor (CAR) T cell therapy in patients with relapsed and/or refractory (R/R) multiple myeloma (MM): first results from a phase 1, multicenter, open-label study. presented at: 64th ASH Annual Meeting and Exposition; December 10-13, 2022 2022; New Orleans, LA.
  12. Park JH, Nath K, Devlin SM, et al. CD19 CAR T-cell therapy and prophylactic anakinra in relapsed or refractory lymphoma: phase 2 trial interim results. Nat Med. 2023;29(7):1710-1717. doi: 10.1038/s41591-023-023404-6.
  13. Dimitri A, Herbst F, Fraietta JA. Engineering the next-generation of CAR T-cells with CRISPR-Cas9 gene editing. Molecular Cancer. 2022;21(1):78. doi:10.1186/s12943-022-01559-z
  14. Frigault MJ, Bishop MR, Rosenblatt J, et al. Phase 1 study of CART-ddBCMA for the treatment of subjects with relapsed and refractory multiple myeloma. Blood Adv. 2023;7(5):768-777. doi:10.1182/bloodadvances.2022007210
  15. Caldwell KJ, Gottschalk S, Talleur AC. Allogeneic CAR cell therapy-more than a pipe dream. Front Immunol. 2020;11:618427. doi:10.3389/fimmu.2020.618427
  16. Ghorashian S, Kramer AM, Onuoha S, et al. Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. Nature Med 2019;25(9):1408-1414. doi:10.1038/s41591-019-0549-5
  17. Shao L, Shi R, Zhao Y, et al. Genome-wide profiling of retroviral DNA integration and its effect on clinical pre-infusion CAR T-cell products. J Translat Med. 2022;20(1):514. doi:10.1186/s12967-022-03729-5

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Discuss advantages and disadvantages of CAR T-cell therapy in hematological malignancies

Describe the opportunities for improvement in CAR T-cell therapy made possible by gene editing techniques.

RELEASE DATE: APRIL 1, 2024

EXPIRATION DATE: APRIL 1, 2025

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Disclosures (Dr Park): Consultant: Allogene, Amgen, Artiva, Autolus, Be Biopharma, BeiGene, Bright Pharmaceutical, Caribou Biosciences, Galapagos, IN8Bio, Kite, Medpace, Minerva Biotechnologies, Pfizer, Servier, Sobi, Takeda; Stockholder: Curocell.

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