CAR-T Therapy in Hematologic Malignancies: A Review of Developments

Introduction

Chimeric Antigen Receptor T-cell (CAR-T) therapy has transformed treatment paradigms for relapsed/refractory hematologic malignancies over the past five years, with seven FDA-approved products generating a global market valued at USD 5.82 billion in 2025 and projected to reach USD 22.36 billion by 203340. Phase III trials demonstrated striking superiority over standard-of-care regimens in multiple myeloma (MM) and diffuse large B-cell lymphoma (DLBCL), with hazard ratios for progression-free survival (PFS) ranging from 0.26 to 0.492. The 2024–2025 period marked significant regulatory evolution, including removal of Risk Evaluation and Mitigation Strategy (REMS) requirements for all approved CD19- and BCMA-targeted products in June 202537, alongside ongoing safety labeling refinements for secondary cancer risk and product-specific toxicities3335. Next-generation platforms—including allogeneic CAR-T with CRISPR-based modifications, dual-target constructs, and novel antigen targeting—have entered clinical development to address manufacturing constraints, antigen escape, and limited durability in heavily pretreated populations528.

1. Technology and Mechanism: CAR Design Evolution

CAR Structure and Generations

CAR-T cells are autologous or allogeneic T lymphocytes genetically engineered to express synthetic receptors combining: (1) an extracellular single-chain variable fragment (scFv) for antigen recognition, (2) a hinge and transmembrane domain, (3) intracellular costimulatory domains, and (4) a CD3ζ signaling domain5.

• Second-generation CARs—incorporating a single costimulatory domain (CD28 or 4-1BB in addition to CD3ζ)—dominate the current commercial landscape. All seven FDA-approved products utilize second-generation constructs525. CD28 costimulation (e.g., axicabtagene ciloleucel/Yescarta) provides rapid T-cell expansion, while 4-1BB (e.g., tisagenlecleucel/Kymriah) confers enhanced persistence5.

• Third-generation CARs integrate dual costimulatory molecules (e.g., CD28 and 4-1BB) to combine rapid activation with sustained persistence5.

• Fourth-generation or "armored" CARs incorporate transgenic cytokine secretion (IL-7, IL-12, IL-15, IL-21) or inducible safety switches (e.g., inducible caspase-9 [iCasp9]) to enhance efficacy and controlled expansion5.

FasT CAR-T platforms achieve manufacturing in 24–36 hours (versus conventional 7–14 days), potentially enabling treatment of rapidly progressive disease, with early products like CD19-CD22 dual-targeted constructs showing promising preliminary efficacy5.

Target Antigens: Approved and Investigational

CD19 remains the dominant target for B-cell malignancies, with four FDA-approved products (Yescarta, Kymriah, Breyanzi, Tecartus) spanning acute lymphoblastic leukemia (ALL), DLBCL, follicular lymphoma (FL), and mantle cell lymphoma (MCL)524. BCMA (B-cell maturation antigen) is the validated target for multiple myeloma, with two approved products (Abecma/idecabtagene vicleucel, Carvykti/ciltacabtagene autoleucel)52.

Emerging targets include CD22 (effective in B-ALL and DLBCL after CD19 failure)1116, CD20 (early encouraging results in B-cell lymphomas)5, GPRC5D (activity in BCMA-refractory MM)21, and BAFF-R/TNFSF13B (novel antigen to address CD19-negative relapse)1. Dual-target strategies (e.g., CD19/CD22, CD19/CD20) are under clinical investigation to mitigate antigen escape mechanisms12131722.

2. Clinical Development by Indication: Efficacy and Safety Benchmarks

Multiple Myeloma: BCMA-Targeted CAR-T

Phase III randomized controlled trials have established BCMA-targeted CAR-T as superior to standard regimens in relapsed/refractory MM (RRMM):

• KarMMa-3 (Abecma vs. standard-of-care): In triple-class exposed RRMM patients (2–4 prior lines), idecabtagene vicleucel achieved median PFS of 13.8 months vs. 4.4 months (HR 0.49, p<0.0001), with overall response rate (ORR) of 71% vs. 41% and complete response (CR) rate of 44% vs. 5%2. Minimal residual disease (MRD) negativity at 6 months was 87% vs. 41%2.

• CARTITUDE-4 (Carvykti vs. standard-of-care): In lenalidomide-refractory MM (1–3 prior lines), ciltacabtagene autoleucel demonstrated median PFS not reached vs. 11.79 months (HR 0.26, p<0.0001), with ORR 85% vs. 67%, CR or better 73% vs. 22%, and MRD negativity 89% vs. 38%2. The 30-month overall survival (OS) rate was 76% vs. 64%2.

Long-term outcomes: The CARTITUDE-1 single-arm trial (median 6 prior lines) reported 5-year follow-up data with ORR 98%, stringent CR 83%, median PFS 34.9 months, median OS 60.6 months, and 5-year PFS of 33%2. MRD negativity (10⁻⁵) was achieved in 92% of patients2.

• Investigational BCMA-targeted products demonstrate competitive efficacy profiles: equecabtagene autoleucel (Fucaso) achieved ORR 96.1%, CR/sCR 77.7%, and 12-month PFS 85.5%2; anito-cel (iMMagine-1) achieved ORR 97%, CR/sCR 68%, and 12-month OS 95.2%2.

Safety: CRS incidence in BCMA-targeted products ranges from 76–95% (any grade) but Grade ≥3 rates are low (0.9–5%)2. ICANS rates are 5–21% (any grade) with Grade ≥3 incidence <10%2. Grade 5 CRS events are rare (<1%)2.

Diffuse Large B-Cell Lymphoma: CD19-Targeted CAR-T in Second-Line

Phase III trials have established CD19-targeted CAR-T superiority over autologous stem cell transplantation (ASCT) in second-line relapsed/refractory DLBCL:

• ZUMA-7 (Yescarta vs. standard-of-care): Axicabtagene ciloleucel achieved median event-free survival (EFS) of 8.3 months vs. 2.0 months (HR 0.398, p<0.0001), with ORR 83% vs. 50%, CR 65% vs. 32%, and 48-month OS 54.6% vs. 46.0%2.

• TRANSFORM (Breyanzi vs. standard-of-care): Lisocabtagene maraleucel demonstrated median EFS of 29.5 months vs. 2.4 months (HR 0.375), with ORR 87% vs. 49%, CR 74% vs. 43%, and 36-month PFS 50.9% vs. 26.5%2.

• BELINDA (Kymriah vs. standard-of-care): Tisagenlecleucel failed to meet its primary endpoint, with median EFS of 3 months in both arms (HR 1.07)2. This negative trial highlighted the importance of manufacturing timelines (around 6 weeks from randomization to infusion on average) and bridging therapy requirements2.

Safety in DLBCL: CD19-targeted products demonstrate CRS incidence of 49–85% (any grade) with Grade ≥3 rates around 1% to 6%2. CRS occurs in half to most patients depending on product; Grade ≥3 CRS is uncommon but varies by construct (e.g., ~1% with liso-cel; ~6% reported in ZUMA-7). Neurologic events/ICANS also vary substantially across products, with higher rates reported with axi-cel and lower severe-event rates in TRANSFORM. 2.

Acute Lymphoblastic Leukemia: CD19-Targeted CAR-T

• ELIANA (Kymriah, pediatric/young adult R/R B-ALL): At 5-year follow-up, overall remission rate was 82%, with CR 60%, 5-year OS 55%, and 5-year EFS 42%2. MRD negativity was achieved in 98% of responders2. Grade 3/4 CRS occurred in 49% with no CRS-related deaths; Grade 3 ICANS in 13%2.

• FELIX (Aucatzyl/obe-cel, adult R/R B-ALL): Overall remission rate was 77%, with CR 55%, median EFS 11.9 months, and median OS 15.6 months2. MRD negativity exceeded 83%2. Grade ≥3 CRS was 2.4% and Grade ≥3 ICANS was 7.1%2.

Dual-target approaches: A phase II trial of CD19/CD22 dual CAR-T in 225 pediatric patients achieved CR in 99% of evaluable patients (all MRD negative), with 12-month EFS of 73.5%22. However, CRS occurred in 88% with 20.9% developing neurotoxicity, including 3 deaths22.

Mantle Cell Lymphoma: CD19-Targeted CAR-T

• ZUMA-2 (Tecartus/brexucabtagene autoleucel): In BTKi-naïve patients, ORR was 91%, CR 73%, and 12-month PFS 75%2. In BTKi-exposed patients, ORR was 91%, CR 67%, with median OS 46.6 months and 5-year OS 39%2. Grade ≥3 CRS ranged from 6–15% and Grade ≥3 ICANS from 21–31% across cohorts2.

3. Approved Products and Competitive Landscape

FDA-Approved Autologous CAR-T Products (as of 2025)

Note: Seven FDA-approved CAR-T products as of late 2025 span 18 distinct indications2423.

Geographic Expansion

USA: Seven approved products with established reimbursement pathways2526.

China: Axicabtagene ciloleucel approved for DLBCL; limited penetration relative to USA (1 vs. 4 approved products in dataset)1. China has over 400 CAR-T therapies in development, predominantly from specialized domestic biotechnology companies43.

EU: Data gaps exist in provided sources; EMA initiated pharmacovigilance review of secondary cancer risk in June 202438.

Autologous vs. Allogeneic Landscape: All approved products are autologous. Allogeneic CAR-T products have entered Phase I/II clinical development with safety and efficacy profiles comparable to autologous therapies29. The first allogeneic CAR-T incorporating CRISPR-based PD-1 knockout has entered clinical testing28.

4. Safety Management and Long-Term Outcomes

Current CRS and ICANS Management Strategies

• CRS Management: Tocilizumab (IL-6 receptor antagonist) is the mainstay therapeutic agent; corticosteroids are used for severe CRS59.

• Prophylactic tocilizumab (administered 1 hour prior to CAR-T infusion) has demonstrated feasibility in a 20-patient cohort, with zero cases of Grade ≥3 CRS and maintained efficacy (75% CR, 1-year OS 83%)4. Anakinra (IL-1 receptor antagonist) can ameliorate both CRS and encephalopathy syndrome514. Ruxolitinib (JAK inhibitor) has shown activity in refractory CRS cases10.

• ICANS Management: Corticosteroids are the primary therapy; tocilizumab has limited efficacy due to poor blood-brain barrier penetration59. Anakinra demonstrated statistically significant reductions in fever and inflammatory cytokines in 14 patients with steroid-refractory ICANS, though clinical neurotoxicity improvement was limited14.

• Grading and Risk Stratification: CRS and ICANS are graded by American Society for Transplantation and Cellular Therapy (ASTCT) criteria9. Higher baseline IL-15 concentrations and post-infusion increases in IL-6, IL-15, IFN-γ, fractalkine, and MCP-1 predict CRS development4.

Long-Term Safety Considerations

• Hematologic toxicity: Grade ≥3 neutropenia (54–99%), anemia (22–62%), and thrombocytopenia (20–53%) are common, with prolonged cytopenias (>28 days) in 14–32% of patients2. Infections: Grade 3/4 infections occur in 6–27%; immunoglobulin supplementation and antimicrobial prophylaxis are standard for hypogammaglobulinemia5.

• Secondary malignancies: In January 2024, the FDA required boxed warnings for T-cell malignancy risk across all approved CAR-T products34. By November 2024, FDA leadership indicated reevaluation of this warning based on emerging evidence35.

• Product-specific toxicities: In October 2025, the FDA added a warning to Carvykti labeling for potentially fatal intestinal disorder risk33. Bilateral anterior cerebral artery occlusion following CD19/BCMA dual-targeted CAR-T has been reported, highlighting the need for cerebrovascular imaging in patients with neuropsychological symptoms8.

• Persistent B-cell aplasia at 6 months post dual CD19/CD22 CAR-T correlated with sustained remission (all 25 patients remained in remission at 12 months)22. Consolidative transplantation following CAR-T improved 12-month EFS to 85% vs. 69.2% in non-transplanted patients in pediatric B-ALL22.

5. Regulatory, Commercial, and Reimbursement Context

Regulatory Evolution (2024–2025)

• REMS program removal: On June 30, 2025, the FDA eliminated REMS requirements for all approved CD19- and BCMA-directed autologous CAR-T therapies, significantly de-risking regulatory burden and reflecting improved safety confidence37. Prior modifications to REMS occurred on June 27, 202436.

• Label expansions: The FDA approved the first CAR-T for marginal zone lymphoma in December 2025, expanding the therapeutic scope23. As of late 2025, seven products are approved for 18 indications, with the FDA reportedly tightening approval requirements for future applications24.

• International harmonization: All seven FDA-approved products have received marketing approval in other major healthcare markets26. The EMA conducted a parallel pharmacovigilance review of secondary cancer risk in June 202438.

Market Access and Adoption

• Global market valuation: The CAR-T market reached USD 5.82 billion in 2025 with projections to USD 22.36 billion by 203340. The broader cell therapy market is projected to expand from USD 8.88 billion (2025) to USD 190.36 billion (2034), exhibiting a CAGR of 40.78%41.

• Pricing: CAR-T products represent the world's most expensive drug class, with costs reaching up to USD 4.5 million per treatment42. This pricing reflects manufacturing complexity and the personalized nature of autologous therapies.

• Geographic disparities: China market penetration remains limited (1 approved product vs. 4 in USA for DLBCL/MCL in dataset)1, suggesting partnership/licensing opportunities for products lacking Asian market access.

6. Emerging Directions and Next-Generation Platforms

Allogeneic CAR-T Development

Allogeneic CAR-T cells derived from healthy donor peripheral blood address manufacturing delays and accessibility limitations inherent in autologous approaches31. Phase I/II trials have demonstrated safety and efficacy profiles comparable to autologous therapy29. Houston Methodist initiated its first allogeneic CAR-T trial in April 2024 for multiple myeloma30. The first allogeneic CAR-T incorporating CRISPR-based PD-1 knockout has entered clinical testing to prevent immune exhaustion28.

CRISPR/Cas9-engineered universal CD19/CD22 dual-targeted CAR-T (CTA101) with TRAC and CD52 gene disruption achieved 83.3% CR rate in Phase I R/R B-ALL with no dose-limiting toxicity, GVHD, or genome editing-associated adverse events7.

Multi-Target and Armored Constructs

Dual-target strategies: CD19/CD22 bivalent CAR-T demonstrated ORR 87.5%, CR 62.5%, and 2-year OS 77.3% in R/R aggressive B-cell lymphoma, with no neurotoxicity12. CD19/CD20 dual-targeting and BCMA/TACI/BAFF-R trispecific approaches are under exploration5.

Fourth-generation CARs: Armored constructs secreting IL-7, IL-12, IL-15, IL-18, or IL-21 to enhance persistence and efficacy are in preclinical/early clinical development5. Safety switches (iCasp9) and small-molecule control systems enable regulated expansion5.

Novel Targets Beyond CD19 and BCMA

GPRC5D-targeted CAR-T (MCARH109) achieved 71% overall response in heavily pretreated MM, including 7/10 patients with prior BCMA therapies, with Grade 4 CRS and ICANS occurring only at the highest dose (450 × 10⁶ cells)21. BAFF-R targeting (PMB-101) addresses CD19-negative relapse in MCL1.

Combination Strategies and FasT Manufacturing

Combinatorial approaches include checkpoint blockade (PD-1/PD-L1 inhibitors), small molecules (lenalidomide, ibrutinib, azacitidine), and radiotherapy as bridging therapy5. FasT CAR-T platforms achieve 24–36 hour manufacturing timelines, potentially suitable for rapidly progressive diseases5.

Actionable Investment and Diligence Takeaways

1. Market Consolidation and Incumbent Moat: Gilead/Kite and BMS/Celgene control the majority of approved CAR-T assets through M&A, with dual-product portfolios and established reimbursement pathways. Regulatory de-risking (REMS removal, June 2025) strengthens incumbent positions and reduces operational complexity371.

2. Efficacy Benchmarks for Competitive Differentiation: Next-generation products must demonstrate >10% absolute improvement in CR rate or >20% improvement in 2-year PFS vs. approved products to achieve differentiation2. Best-in-class BCMA-targeted products achieve ORR >85%, CR >70%, and median PFS >30 months; best-in-class DLBCL products achieve median EFS >25 months with 3-year PFS >50%2.

3. Safety Profile Thresholds: Acceptable CRS/ICANS profiles require Grade ≥3 CRS <5% and Grade ≥3 ICANS <10%2. Products exceeding these thresholds face competitive disadvantage absent superior efficacy or differentiated mechanism.

4. Allogeneic Platform Opportunity: Allogeneic CAR-T with gene-editing represents highest-risk/highest-reward investment thesis for manufacturing cost reduction and off-the-shelf availability, but remains unproven at commercial scale with regulatory and GVHD risk28291.

5. China Market Expansion Potential: China's >400 CAR-T development programs and limited current penetration (1 approved product vs. 4 in USA for DLBCL/MCL) represent significant geographic arbitrage opportunity for established products and partnership/licensing deals with domestic innovators431.

Conclusion

CAR-T therapy has achieved clinical validation across multiple hematologic malignancies over the past five years, with Phase III data demonstrating dramatic superiority over standard-of-care regimens and durable long-term responses in subset populations. The 2024–2025 period marked regulatory maturation (REMS removal, label expansions) and safety labeling refinements, alongside market expansion to USD 5.82 billion globally. Competitive differentiation now requires superior efficacy benchmarks, improved safety profiles (particularly Grade ≥3 CRS/ICANS <5–10%), or platform innovation (allogeneic, gene-editing, multi-target). Key investment diligence priorities include assessment of manufacturing timelines, antigen escape mitigation strategies, real-world durability data, and geographic expansion potential in underpenetrated markets such as China.