33 Adoptive Cellular Therapy
- CAR-T cell therapy: Engineered T cells w/ chimeric antigen receptor (CAR) targeting CD19 or BCMA for hematologic malignancies & solid tumors
- CAR-T mechanisms: Engage cognate antigen in MHC-independent manner w/ unique toxicities (CRS, ICANS) vs conventional immunotherapy
- FDA-approved products: Tisagenlecleucel, axicabtagene ciloleucel, idecabtagene vicleucel (CD19-directed); teclistamab, talquetamab (BCMA-directed)
- CRS/ICANS: On-target effects w/ incidence 50-90%, graded by severity; management includes monitoring, supportive care, tocilizumab, corticosteroids
- Indication expansion: Approved for B-cell ALL, DLBCL, FL, mantle cell lymphoma, MM; clinical trials for solid tumors ongoing
33.1 Introduction
Adoptive cellular therapies leverage immune system for malignancy treatment: - Modalities: TILs, CAR-T cells, allogeneic HCT, NK cells - Focus: CAR-T & other engineered therapies (HCT covered separately)
33.2 Cancer Therapy with Chimeric Antigen Receptor-Modified T Cells
33.2.1 CAR Design & Engineering
CAR structure: scFv (antibody), spacer/hinge, TCR CD3ζ, costimulatory domain
Generation comparison: - Gen 1: Limited expansion, persistence, antitumor activity - Gen 2: + costimulatory domain (CD28 or 4-1BB); improved signaling - Gen 3+: Dual costimulatory, enhanced persistence & antitumor effects
Manufacturing & infusion: - Source: Autologous T cells (current FDA-approved); allogeneic (investigational) - Transduction: Lentiviral or gamma-retroviral vectors; mRNA electroporation - Ex vivo expansion: Tregs removed, IL-2 stimulation - Lymphodepletion: Fludarabine + cyclophosphamide pre-infusion - Post-infusion: CAR-T recognize antigen → activation → rapid proliferation → risk of exhaustion
Allogeneic CAR-T (investigational): - Advantages: Ready-made product, reduced manufacturing time - Concerns: Risk of rejection; off-tumor effects; GVHD - Status: No FDA-approved allogeneic products yet - Engineering: Attempt to remove GvHD while preserving GvT
33.2.2 TCR-Engineered T Cells
- Recognize peptides presented on MHC (antigen-presenting cells required)
- Limitations: Less flexible than CAR-T, requires MHC matching
- Concerns: Off-target effects from cross-reactive TCRs
- Less developed than CAR-T for clinical use
33.3 Natural Killer Cells
NK cell features: - Antigen-independent killing; no GVHD - Intrinsic balance: Activating & inhibitory receptors - Antimicrobial & antitumor functions
Current development: - Source: Allogeneic (peripheral blood, umbilical cord) - Ex vivo expansion: Selection & activation protocols - Lymphodepletion: Fludarabine may enhance persistence via IL-15 - CAR NK cells: Engineered NK w/ CAR constructs (investigational) - Safety: No reported CRS or chronic GVHD (vs CAR-T, TIL)
33.4 Tumor-Infiltrating Lymphocytes
- Source: Patient’s own tumor-resident lymphocytes
- Process: Harvest → ex vivo expansion → reinfusion w/ lymphodepletion & low-dose IL-2
- Indications: Refractory solid tumors (melanoma, cholangiocarcinoma, NSCLC)
- Response rates: ORR 30-56% in metastatic melanoma
- FDA-approved: Lifileucel (unresectable/metastatic melanoma)
33.5 Adoptive Cellular Therapy Complications
33.5.1 Cytokine Release Syndrome & Immune Effector Cell-Associated Neurotoxicity Syndrome
CRS pathophysiology: - Systemic inflammatory response after CAR-T activation & expansion - IL-6 characteristic; correlates w/ neurotoxicity risk - Incidence: 50-90% CD19-directed; 30-50% BCMA-directed - Can be severe or fatal
ICANS pathophysiology: - Distinct neurotoxicity syndrome (not CRS in CNS) - Mechanism incompletely understood - Incidence: 20-50% CD19-directed; variable BCMA-directed - Can progress rapidly to cerebral edema, seizures, death
33.5.1.1 CRS Grading & Management
| Grade | Fever | Hypotension | Hypoxia | Management |
|---|---|---|---|---|
| 1 | ≥38.3°C | None | None | Supportive care |
| 2 | ≥38.3°C | Responsive to fluids/low-dose vasopressor | <95% responsive to O₂/low-flow | Tocilizumab or steroids |
| 3 | ≥38.3°C | Unresponsive/high-dose vasopressor ± altered mentation | <90% or intubation not for CRS | Tocilizumab ± high-dose steroids |
| 4 | ≥38.3°C | Refractory despite vasopressors ± arrhythmias | <90% on mechanical ventilation | Tocilizumab + steroids; consider ICU support |
CRS management: - Monitor: Fever, hemodynamics, oxygenation; serial labs (CRP, IL-6, ferritin) - Supportive: Fluids, vasopressors, supplemental O₂, mechanical ventilation - IL-6 antagonist: Tocilizumab (IL-6 receptor antagonist) for G2+ CRS - Corticosteroids: High-dose for G3+; less effective for G1-2 - Note: Treat CRS quickly; may improve CAR-T efficacy
33.5.1.2 ICANS Grading & Management
| Grade | Findings |
|---|---|
| 1 | Mild: tremor, headache, mild confusion |
| 2 | Moderate: disorientation, slowed speech/response w/o seizures; focal neurologic signs |
| 3 | Severe: altered mental status, language disturbance, seizures, focal deficits |
| 4 | Life-threatening: cerebral edema, status epilepticus, stroke, intracerebral hemorrhage |
ICANS assessment: - ICE score: Orientation, naming, following commands (0-4 points; ≥2 = potential ICANS) - Neuroimaging: MRI for cerebral edema, hemorrhage; LP rarely needed - EEG: If seizures or unexplained altered mental status
ICANS management: - Corticosteroids: High-dose dexamethasone or methylprednisolone (first-line for G2+) - Tocilizumab: May help in select cases; less data than CRS - Supportive: Seizure prophylaxis (levetiracetam), ventilation if needed - Neurology consult: Essential for G2+ or diagnostic uncertainty - Note: Monitor closely; can deteriorate rapidly
33.5.2 Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome
- Distinct from CRS & ICANS: Macrophage activation syndrome
- Presentation: Hemophagocytosis, hyperinflammation, cytopenias, ↑ferritin/LDH, ↓fibrinogen
- Incidence: <5% post-CAR-T
- Management: Tocilizumab, steroids, IVIG; management evolving (2023 ASTCT consensus published)
33.5.3 Long-term Side Effects Following CAR-T-Cell Therapy
- Cytopenias: Grade 3-4 cytopenias in 30-50% at 3-12 mo post-infusion; recovery variable
- Secondary malignancies: T-cell lymphomas, other malignancies (incidence <2% but increase w/ longer follow-up)
- Infections: Grade 3+ infections 30-50%; fungal, viral, bacterial (CMV, EBV reactivation)
- Hypogammaglobulinemia: Prolonged in some patients; IVIG support sometimes needed
- Monitoring: Long-term follow-up essential; limited data >5 years
33.5.4 CD19-Targeted CAR-T-Cell Therapy for B-Cell Acute Lymphoblastic Leukemia
Tisagenlecleucel (Kymriah, CTL019): - Design: 4-1BB costimulatory, CD3ζ, lentiviral transduction - Trial: ELIANA (n=75, age 3-23 y, relapsed/refractory B-ALL) - CR rate: 90%; 3-y RFS: 50%; 3-y OS: 76% - CRS: 87% (G3-4: 24%); ICANS: 71% (G3-4: 19%) - Deaths: 2 (airway obstruction, brain hemorrhage)
Approval: FDA approved 2017 (pediatric B-ALL); 2018 (adult B-ALL)
Adult data (University of Pennsylvania): - n=29 high-dose infusion - CR: 90%; 2-y OS: 73%; 2-y EFS: 50% - CRS: 55% (G3-4); ICANS: 64% (G3-4: 28%)
33.5.5 CD19-Targeted CAR-T-Cell Therapy in Diffuse Large B-Cell Lymphoma
Axicabtagene ciloleucel (Yescarta): - Design: CD28 costimulatory, gamma-retroviral transduction - Trial: ZUMA-1 (n=101, relapsed/refractory LBCL, ≥2 prior lines) - ORR: 81%; CR: 54%; 12-mo EFS: 50%; 12-mo OS: 76% - CRS: 93% (G3-4: 13%); ICANS: 64% (G3-4: 13%)
Tisagenlecleucel (Kymriah): - Trial: JULIET (n=93, age ≥18 y, relapsed/refractory LBCL) - ORR: 82%; CR: 53%; median response duration: 12 mo - CRS: 7-22% (G3-4); ICANS: 8% (G3-4) - Approval: Second-line for LBCL (2018)
33.5.6 CD19-Targeted CAR-T-Cell Therapy in Follicular Lymphoma
- Tisagenlecleucel: FDA-approved for FL after ≥2 prior lines
- Trial data: ORR 91%, CR 100% at 18 mo (excellent long-term remissions)
- Toxicities: CRS 8% (G3+); ICANS 21% (G3+) (lower than B-ALL, DLBCL)
- Note: Earlier treatment being explored in clinical trials
33.5.7 CAR-T-Cell Therapy for Multiple Myeloma
BCMA-targeted therapies:
Idecabtagene vicleucel (Abecma): - Design: 4-1BB costimulatory - Trial: IDE3A01 (n=128, relapsed/refractory MM, ≥3 prior lines) - ORR: 73%; CR: 33%; median OS: not reached at median follow-up - CRS: 43% (G3-4: 5%); ICANS: 29% (G3-4: 7%)
Teclistamab (Tecartus): - Design: Bispecific anti-BCMA/anti-CD3 (not CAR-T); dual 4-1BB signaling - ORR: 73%; CR: 32%; 3-y OS: ~50% - Toxicities: CRS 49% (G3-4: 5%); ICANS 10% (G3-4: 2%)
Talquetamab-tgvs (Talquetamab): - Design: GPRC5D-targeted bispecific - Status: Emerging data; multi-organ dysfunction in some; favorable ORR
MM-specific considerations: - Rapid infusion allowed (vs CD19-directed w/ slower escalation) - Deeper responses possible w/ BCMA vs GPRC5D - Risk of extramedullary disease relapses
- Pre-infusion screening: HBV, HCV, HIV, TB; CNS disease; active infection; adequate organ function
- CRS/ICANS monitoring: Daily exams post-infusion; tocilizumab ± steroids highly effective; early intervention prevents escalation
- CAR-T selection:
- CD19: B-ALL (90% CR), DLBCL (50-80% CR), FL (indolent response)
- BCMA: MM only; relapsed/refractory w/ ≥3 prior lines
- Response assessment: PET/CT or bone marrow at 3-4 wk post-infusion
- Bridge therapy: Often needed during manufacturing (4-6 wk); avoid allogeneic HCT if possible
- Long-term follow-up: Monitor cytopenias, infections, secondary malignancies; immune reconstitution variable
33.6 CAR-T Cell Products
| Product | Target | Indication | Costimulatory | Vector | Source |
|---|---|---|---|---|---|
| Tisagenlecleucel (Kymriah) | CD19 | B-ALL, DLBCL, FL, MCL | 4-1BB | Lentiviral | Autologous |
| Axicabtagene ciloleucel (Yescarta) | CD19 | DLBCL, PMBCL, TFL | CD28 | Gamma-retroviral | Autologous |
| Lisocabtagene ciloleucel (Jcarh016, likely coming) | CD19 | LBCL | 4-1BB | Lentiviral | Autologous |
| Brexucabtagene autoleucel (Tecartus for MCL) | CD19 | MCL | 4-1BB | Lentiviral | Autologous |
| Idecabtagene vicleucel (Abecma) | BCMA | Relapsed/refractory MM (≥3 prior) | 4-1BB | Lentiviral | Autologous |
| Teclistamab (Tecartus, bispecific) | BCMA/CD3 | Relapsed/refractory MM (≥2 prior) | Dual 4-1BB | — | Autologous |
| Talquetamab (talquetamab-tgvs) | GPRC5D/CD3 | Relapsed/refractory MM (≥1 prior) | Dual 4-1BB | — | Autologous |
33.7 Bibliography
Ardeshna KM, Qian W, et al. Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial. Lancet Oncol. 2014;15:424-435.
Baldassa L, Hamidreza M, Wolanskyj A, et al. Genomic-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in pediatric relapsed/refractory acute lymphoblastic leukemia. Nat Med. 2020;26:296-306.
Hay K, Chemaly RF, Levine BL, et al. Efficacy of infectious disease management strategy in patients undergoing CAR T-cell therapy for hematologic malignancies. Blood. 2019;134:2913-2924.
Hingorani M, Knight TN, Neunzig ICD et al Immune effector cell-associated neurotoxicity syndrome. Blood. 2019;134:2585-2597.
Hugo BP, et al. Risk of second tumors and T-cell lymphoma after CAR-T therapy in childhood and young adults. N Engl J Med. 2020;382:545-555.
Meeth KM, Larrick TN, et al. Tisagenlecleucel in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia. Blood. 2018;378(9):449-481.
Neelapu SS, Rossi JM, et al. Outcomes of Relapsed or Refractory Large B-Cell Lymphoma Treated With Chimeric Antigen Receptor T-Cell Therapy. Blood. 2018;131(16):1547-1552.
Reusch U, Sundaram H, Davol PA, et al. Mechanism of action and in vitro efficacy of a novel anti-CD33/CD3 bispecific antibody (AMG 330) in acute myeloid leukemia cells. Mol Cancer Ther. 2016;15:2826-2838.
Rodriguez-Otero P, Aldarondo J, et al. Mid-level of standard responders in relapsed and refractory multiple myeloma. N Engl J Med. 2023;388(11):1002-1014.
Roshon MW, Patel J, van den Berg JH, et al. Tumor-infiltrating lymphocyte therapy or ipilimumab in advanced melanoma. N Engl J Med. 2022;387(23):2113-2123.
Shah NN, Johnson BD, Schneider D, et al. Bispecific anti-CD19, anti-CD3 bispecific T-cell engagers. Blood. 2020;135(21):1883-1894.
Shah NN, Maatman T, Pillai RK et al Targeted CAR-T-cell therapies for B-cell malignancies: phase 1 study result. Blood Oncol. 2019;9:146.
Smith M, Zakrzewski J, James S, Sukdalan M. Domrantipan chimeric antigen receptor therapy. Blood. 2018;131(16):1545-1552.
Worsnop JR, Olmedo CG, Kerwin MJ, et al. Survival w/ axi-cel introduced in large B-cell lymphomas. N Engl J Med. 2023;389(2):148-157.
Zetser R, Palharvi N, Kum R, et al. Rasutonib for glucocorticoid-refractory chronic graft-versus-host disease. N Engl J Med. 2021;385(3):228-238.
Zetser R, von Bubnoff N, Budler J, et al. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N Engl J Med. 2020;19:1800-1810.