History of CAR-T Cell Therapy in Hematologic Malignancies
CAR-T cell therapy represents a revolutionary advancement in cancer treatment that emerged from decades of immunotherapy research, with the first FDA approval occurring in 2017 for tisagenlecleucel (Kymriah) in pediatric and young adult B-cell acute lymphoblastic leukemia, marking a paradigm shift from traditional chemotherapy to genetically engineered "living drugs." 1, 2
Early Development and Conceptual Foundation
The foundational concept of CAR-T therapy evolved from early adoptive cell therapy approaches that attempted to induce graft-versus-leukemia effects through allogeneic hematopoietic stem cell transplantation (HSCT) and donor lymphocyte infusions 1. However, these methods carried significant risks of graft-versus-host disease, prompting researchers to explore using patients' own T cells engineered to target malignant cells 1.
The breakthrough came with the ability to genetically reprogram T cells to express synthetic chimeric antigen receptors (CARs) that could recognize tumor-specific antigens independent of major histocompatibility complex (MHC) presentation 3, 4. This HLA-independent targeting mechanism represented a critical advantage over conventional T-cell therapies 3.
Receptor Design Evolution
CAR constructs evolved through multiple generations, with the structure comprising an extracellular antigen recognition domain, hinge region, transmembrane domain, and intracellular signaling domains 3. The most successful designs incorporated costimulatory domains—either CD28 (termed 19-28z construct) or 4-1BB (termed CTL019)—linked to CD3 zeta for T-cell activation 1, 3.
Early clinical trials demonstrated the superiority of these costimulatory-enhanced CARs, with the 19-28z construct showing overall complete remission in 14 of 16 patients with relapsed/refractory B-cell ALL, and the CTL019 construct achieving complete remission in 27 of 30 patients (90%) 1.
Target Antigen Selection: CD19 as the Pioneer
CD19 in B-Cell Malignancies
CD19 emerged as the ideal initial target because it is expressed on all B cells throughout development, retained on neoplastic B cells, and increased in expression on most B-cell tumors including B-cell ALL, chronic lymphocytic leukemia, and B-cell lymphomas 1. This consistent expression pattern made CD19 a reliable biomarker for targeting malignant B cells 1.
The first approved CD19-directed CAR-T products included tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel, and lisocabtagene maraleucel 1, 3.
Landmark Clinical Trials and FDA Approvals
Pediatric and Young Adult ALL (2017)
The ELIANA trial of CTL019 (tisagenlecleucel) in 62 children and young adults with relapsed/refractory B-ALL demonstrated an 83% complete remission rate with complete blood count recovery, with all responses being MRD-negative 1. This translated to a 6-month relapse-free survival rate of 75% and 6-month overall survival of 89%, with treatment-related mortality remaining low at 6% despite severe cytokine release syndrome and neurologic toxicity 1.
These results led to FDA Oncologic Drug Advisory Committee recommendation for accelerated approval in July 2017, culminating in the first FDA approval of a CAR-T product 1, 2.
Adult Large B-Cell Lymphoma
CAR-T therapy expanded to adult relapsed/refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy, with subsequent approvals for high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma 3, 2. The ZUMA-1 and JULIET trials established efficacy in this population, though CNS involvement was initially an exclusion criterion 1.
Mantle Cell Lymphoma and Follicular Lymphoma
The ZUMA-2 trial led to approval for mantle cell lymphoma, with CNS involvement remaining an exclusion 1. Follicular lymphoma received accelerated approval after two or more lines of systemic therapy, though continued approval remains contingent on confirmatory trial verification 2.
Expansion to Multiple Myeloma: BCMA Targeting
BCMA as a Novel Target
B-cell maturation antigen (BCMA) emerged as the second major CAR-T target, expressed on mature B cells and plasma cells but not naïve B cells or other hematopoietic cells 1. BCMA promotes plasma cell survival in bone marrow, and serum BCMA levels are elevated in multiple myeloma patients compared to those without disease 1.
Idecabtagene vicleucel became the first BCMA-targeted CAR-T therapy approved in 2021 for multiple myeloma, with ciltacabtagene autoleucel subsequently under FDA consideration 1, 3.
Manufacturing Process and Logistics
The CAR-T manufacturing process requires leukapheresis to collect white blood cells, followed by T-cell isolation, activation, and genetic modification using viral vectors (typically lentiviral or retroviral), with expansion over several days to weeks to produce sufficient cell numbers 1, 3. The engineered cells are then cryopreserved and shipped back to the treatment center 3.
Prior to infusion, patients undergo lymphodepletion chemotherapy—typically fludarabine and cyclophosphamide—to prevent immunologic rejection and maximize CAR-T expansion and persistence 1, 3. This "vein-to-vein" time between leukapheresis and infusion typically spans 4-6 weeks 1.
Bridging Therapy Development
Bridging therapy administered during the 4-6 week manufacturing period aims to reduce disease burden, increase CAR-T efficacy, improve intention-to-treat outcomes, and reduce immunotoxicity 1. Options include high-dose chemotherapy, low-dose chemotherapy, radiotherapy, and novel agents, with patient-specific recommendations made by multidisciplinary teams 1.
Bridging can be omitted when vein-to-vein time is short and disease burden is low 1.
Toxicity Recognition and Management Evolution
Cytokine Release Syndrome (CRS)
CRS emerged as the signature toxicity of CAR-T therapy, characterized by fever, hypotension, and potentially life-threatening organ dysfunction occurring within the first 2 days after infusion 1, 3. The incidence of adverse events can be reduced with monitoring for early intervention 1.
Tocilizumab, an anti-IL-6 therapy, became the cornerstone of CRS management, with dosing at 8 mg/kg IV over 1 hour (not exceeding 800 mg), repeatable every 8 hours if no improvement, with a maximum of 3 doses 1. Corticosteroids are added for refractory cases 1.
Neurological Toxicities
Neurologic toxicities (CAR-T cell-related encephalopathy syndrome) occur in approximately 50% of patients with median onset at 7 days, though can occur 1-2 weeks post-infusion with late onset possible up to a month later 1, 3. Grade 3 or higher neurologic toxicities including encephalopathy, convulsions, and disorientation occur in 15% of patients 1.
REMS Program Implementation
Due to these severe toxicities, tisagenlecleucel is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS) program called the KYMRIAH REMS 2. This requires certified healthcare facilities with trained personnel and immediate access to tocilizumab 2.
Secondary Malignancies Recognition
A critical safety signal emerged in 2024: T-cell malignancies have occurred following treatment with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies, including KYMRIAH, leading to a boxed warning addition 2. This represents an evolving understanding of long-term CAR-T risks 2.
Clinical Practice Integration
Patient Selection Criteria Evolution
Prior allogeneic HCT is not a contraindication to CAR-T therapy when patients are off immunosuppression, though in ALL it may increase risk of CAR-T-associated toxicity 1. Active infections (bacterial, fungal, or viral) require deferral until controlled, though latent infections like HIV, HBV, or HCV can proceed with prophylactic antiviral treatment 1.
CNS involvement evolved from an absolute exclusion to a relative contraindication requiring careful risk-benefit assessment, with real-world evidence in DLBCL suggesting CAR-T is well-tolerated and potentially efficacious 1.
Outpatient Administration Development
Outpatient CAR-T administration became feasible by 2022, provided clear policies, appropriate infrastructure, well-trained staff, and capacity for 24/7 hospitalization exist 1. However, hospitalization typically remains recommended for adult patients for at least 4 weeks post-infusion 3.
Antigen Escape and Re-treatment Strategies
Prior treatment with bispecific antibodies or prior CAR-T is not a contraindication, but antigen-negative escape must be excluded at relapse before proceeding, especially in B-cell ALL 1. Reduced CD19 expression may not decrease anti-CD19 CAR-T efficacy in B-ALL, though prior blinatumomab treatment may impair efficacy 1.
A second infusion of anti-CD19 CAR-T cells can induce remission in a subset of patients, and in multiple myeloma, re-treatment with anti-BCMA CAR-T is possible 1.
Current Limitations and Ongoing Challenges
The manufacturing process remains complex and logistically challenging, with significant barriers including manufacturing limitations, toxicity concerns, and substantial financial burden limiting widespread accessibility 3, 5. The therapy has not achieved similar success in solid tumors due to heterogeneous tumor antigen expression and immunosuppressive tumor microenvironments 6.
Future Directions
Allogeneic "off-the-shelf" CAR-T products are under development to reduce manufacturing time and costs, potentially addressing current logistical barriers 3. Research continues on novel targets beyond CD19 and BCMA, strategies to overcome CAR-T dysfunction, and approaches to enhance efficacy in currently resistant malignancies like acute myeloid leukemia 4, 7.