The Role of Chimeric Antigen Receptor-T Cell Therapy in the Treatment of Hematological Malignancies: Advantages, Trials, and Tribulations, and the Road Ahead

Abstract

Immunotherapy is the upcoming trend in cancer treatment. Traditional cancer treatment methods include surgical resection, radiotherapy, chemotherapy, small molecule targeted drugs, monoclonal antibodies, and hematopoietic stem cell transplantation (HSCT). Surgical resection is useful for early-stage patients but not for metastatic cancer cells; radiotherapy and chemotherapy are more common but produce substantial damage to normal tissues and have poor selectivity. Targeted drugs, including monoclonal antibodies, have better comprehensive efficacy but can also encourage gene mutation of tumor cells and drug tolerance. HSCT is effective, but choosing a donor is often difficult, and the graft is also prone to rejection. Thus, chimeric antigen receptor (CAR)-T cell therapy, a form of cellular/adoptive immunotherapy, is at the forefront of cancer therapy treatments due to its sustained remission, fewer side effects, and a better quality of life. CAR-T cell therapy involves genetically modifying the T cells and multiplying their numbers to kill cancer cells. This review article gives an insight into how the CAR-T cells have evolved from simple T cells with modest immune function to genetically engineered robust counterparts that brought great hope in the treatment of hematological malignancies. Much research has been undertaken during the past decade to design and deliver CAR-T cells. This has led to successful outcomes in leukemias, lymphomas, and multiple myeloma, paving the way for expanding CAR therapy. Despite tremendous progress, CAR-T cell therapies are faced with many challenges. Areas for improvement include limited T cell persistence, tumor escape, immunosuppressive components in the tumor microenvironment, cancer relapse rate, manufacturing time, and production cost. In this manuscript, we summarize the innovations in the design and delivery of CAR technologies, their applications in hematological malignancies, limitations to its widespread application, latest developments, and the future scope of research to counter the challenges and improve its effectiveness and persistence.

A comprehensive regulatory and industry review of modeling and simulation practices in oncology clinical drug development

“…Among several CGT modalities, Chimeric Antigen Receptor (CAR) T cell-based therapy has shown clinical benefits in different cancer types [ 151 , 152 ]. In this treatment, a patient’s T-cells are modified in the laboratory and specific CARs are introduced to the surface of the T-cell in order to target very specific malignant cancer cells.…”

Progress and prospect of ASCT combined with CAR-T therapy in the treatment of multiple myeloma

“… 34 CAR-T, as a ‘living drug’, propagates in patients, recognizes cancer cells with specific antigens, and kills tumor cells through apoptosis mediated by granzyme/perforin, which enables it to continue to play its role. 35 While, its limitations cannot be ignored. Even patients who respond to CAR-T therapy in the hematologic setting are still at risk of recurrence, which is due to several factors, including poor expansion of T cells, lack of long-term durability after adoptive transplantation, and excessive inhibitory determinants in the TME leading to T cell failure.…”

O Futuro Da Imunoterapia: Car-T Uma Inovadora Terapia Na Onco-Hematologia E Suas Limitações Para Tumores Sólidos

“…No grau 1 é feito apenas um tratamento de suporte para aliviar os sintomas, no grau 2, 3, e 4 é administrado o medicamento Tocilizumabe que atua bloqueando os receptores da Interleucina 6 , e corticosteroides, além desses também podem ser utilizados um inibidor de GM-CSF a fim de impedir que as células mieloides e as células T se infiltrem, e pode potencializar a ação antitumoral das células CAR-T.O medicamento Anakinra que bloqueia receptores da Interleucina 1 também é usado no tratamento. 15 Alguns fatores influenciam na gravidade da SRC como características do câncer hematológico, a carga tumoral, estrutura do CAR, e doses das células CAR-T. Embora a SRC seja um evento adverso grave, dependendo do grau, foi observado que os pacientes que apresentaram SRC acima do grau 2 obtiveram altas taxas de remissão e ficaram livre da progressão da doença, em comparação com os pacientes que tiveram a SRC em um grau mais brando. Com isso é possível constatar que a Síndrome de Liberação de Citocinas, de uma forma controlada pode ajudar na atuação das células CAR-T. O diagnóstico de SRC é um indicativo que as células CAR-T estão em atividade atacando o alvo.…”