From CAR-T Cells to CAR-NK Cells: A Developing Immunotherapy Method for Hematological Malignancies

The advent of chimeric antigen receptor (CAR) T-cell therapy has led to dramatic remission rates in multiple relapsed/refractory hematologic malignancies. While CAR T-cell therapy has been particularly successful as a treatment for B-cell malignancies, effectively treating acute myeloid leukemia (AML) with CARs has posed a larger challenge. AML not only creates an immunosuppressive tumor microenvironment that dampens CAR T-cell responses, but it also lacks many unique tumor-associated antigens, making leukemic-specific targeting difficult. One advantage of CAR T-cell therapy compared to alternative treatment options is the ability to provide prolonged antigen-specific immune effector and surveillance functions. Since many AML CAR targets under investigation including CD33, CD117, and CD123 are also expressed on hematopoietic stem cells, CAR T-cell therapy can lead to severe and potentially lethal myeloablation. Novel strategies to combat these issues include creation of bispecific CARs, CAR T-cell “safety switches”, TCR-like CARs, NK CARs, and universal CARs, but all vary in their ability to provide a sustained remission, and consolidation with an allogeneic hematopoietic cell transplantation (allo-HCT) will be necessary in most cases This review highlights the delicate balance between effectively eliminating AML blasts and leukemic stem cells, while preserving the ability for bone marrow to regenerate. The impact of CAR therapy on treatment landscape of AML and changing scope of allo-HCT is discussed. Continued advances in AML CAR therapy would be of great benefit to a disease that still has high morbidity and mortality.

Section: Issues With Quality Of Autologous Cellsmentioning

confidence: 99%

Challenges and Advances in Chimeric Antigen Receptor Therapy for Acute Myeloid Leukemia

Marvin-Peek

Savani

Oluwole

et al. 2022

“…Besides CAR T cells, CAR-NK cells against BCMA (e.g., FT576, NK92, UCB), CD38, SLAMF7 and NKG2D are under development with the potential advantage of multiple off-the-shelf sources, lower toxicity and mode-of-actions via CAR but also endogenous receptors [71,72]. Clinical trials have already been initiated (e.g., NCT03940833, NCT05008536) [73].…”

Section: Chimeric Antigen Receptor T Cells (Car T Cells)mentioning

confidence: 99%

Relapsed/Refractory Multiple Myeloma in 2020/2021 and Beyond

Podar

Leleu

2021

Despite the challenges imposed by the COVID-19 pandemic, exciting therapeutic progress continues to be made in MM. New drug approvals for relapsed/refractory (RR)MM in 2020/2021 include the second CD38 monoclonal antibody, isatuximab, the first BCMA-targeting therapy and first-in-class antibody–drug conjugate (ADC) belantamab mafodotin, the first BCMA-targeting CAR T cell product Idecabtagen-Vicleucel (bb2121, Ide-Cel), the first in-class XPO-1 inhibitor selinexor, as well as the first-in-class anti-tumor peptide-drug conjugate, melflufen. The present introductory article of the Special Issue on “Advances in the Treatment of Relapsed and Refractory Multiple Myeloma: Novel Agents, Immunotherapies and Beyond” summarizes the most recent registration trials and emerging immunotherapies in RRMM, gives an overview on latest insights on MM genomics and on tumor-induced changes within the MM microenvironment, and presents some of the most promising rationally derived future therapeutic strategies.

“…Therefore, CAR-NK cells may also handle as a bridge strategy, through which patients can accomplish a low pre-infusion minimal residual disease (MRD) condition before administration of allo-HSCT. The aim of NCT02892695 clinical trial is to figure out the safety and best dose of CD19 CAR-NK cells used as a bridge therapy in patients who intend to undergo HSCT [129].…”

Section: State Of the Art Of Nk Cell Therapies And Cd19-car-nk Therapies With The Recent Clinical Trial Data In Refractory B Malignanciesmentioning

confidence: 99%

The Race of CAR Therapies: CAR-NK Cells for Fighting B-Cell Hematological Cancers

Herrera

Santos

Vesga

et al. 2021

Acute lymphoblastic leukemia (ALL) and Chronic lymphocytic leukemia (CLL) are the most common leukemias in children and elderly people, respectively. Standard therapies, such as chemotherapy, are only effective in 40% of ALL adult patients with a five-year survival rate and therefore new alternatives need to be used, such as immunotherapy targeting specific receptors of malignant cells. Among all the options, CAR (Chimeric antigen receptor)-based therapy has arisen as a new opportunity for refractory or relapsed hematological cancer patients. CARs were designed to be used along with T lymphocytes, creating CAR-T cells, but they are presenting such encouraging results that they are already in use as drugs. Nonetheless, their side-effects and the fact that it is not possible to infuse an allogenic CAR-T product without causing graft-versus-host-disease, have meant using a different cell source to solve these problems, such as Natural Killer (NK) cells. Although CAR-based treatment is a high-speed race led by CAR-T cells, CAR-NK cells are slowly (but surely) consolidating their position; their demonstrated efficacy and the lack of undesirable side-effects is opening a new door for CAR-based treatments. CAR-NKs are now in the field to stay.