CAR T-cell and other cellular therapies

Pharmacology·CAR-T·2021

Tisagenlecleucel (Kymriah)

— CD19/scFv/4-1BB-CD3ζ
FDA Aug 2017 pediatric/young adult (≤25 yo) B-ALL that is refractory or in 2nd+ relapse (ELIANA); FDA May 2018 R/R DLBCL after ≥2 LOT (JULIET); FDA May 2022 R/R FL after ≥2 LOT (ELARA — Fowler Nat Med 2022).

Axicabtagene ciloleucel (Yescarta)

— CD19/scFv/CD28-CD3ζ
FDA Oct 2017 R/R DLBCL ≥2 LOT (ZUMA-1); FDA Apr 1, 2022 expanded to 2L for primary refractory or early relapse (≤12 mo) DLBCL (ZUMA-7); FDA Mar 5, 2021 R/R FL ≥2 LOT (ZUMA-5).

Brexucabtagene autoleucel (Tecartus)

— CD19/scFv/CD28-CD3ζ
FDA Jul 2020 R/R MCL (ZUMA-2; label does not require prior BTKi; ORR 93%, CR 67%); FDA Oct 2021 adult R/R B-ALL (ZUMA-3; CR/CRi 71%).

Lisocabtagene maraleucel (Breyanzi)

— CD19/scFv/4-1BB-CD3ζ (defined CD4:CD8 = 1:1)
FDA Feb 2021 R/R DLBCL ≥2 LOT (TRANSCEND NHL 001); FDA Jun 2022 expanded to 2L (TRANSFORM); FDA Mar 14, 2024 R/R CLL/SLL after BTKi + BCL2i (TRANSCEND CLL 004; first CAR-T for CLL); FDA May 15, 2024 R/R FL ≥2 LOT (TRANSCEND FL; ORR 95.7%, CR 73.4% (FDA 3L+ efficacy set)); FDA May 30, 2024 R/R MCL after ≥2 prior lines incl BTKi (TRANSCEND NHL 001 MCL cohort); FDA Dec 4, 2025 R/R MZL ≥2 LOT (TRANSCEND FL-MZL; first CAR-T for MZL).

Obecabtagene autoleucel (Aucatzyl, obe-cel)

— CD19/scFv/4-1BB-CD3ζ with fast-off-rate CD19 binder → less T-cell exhaustion, lower CRS/ICANS

FDA Nov 8, 2024

for adult R/R B-cell precursor ALL (FELIX — Roddie NEJM 2024; ORR 76%, CR 54%, CRi 21%; G≥3 CRS 3%, G≥3 ICANS 7%). First CAR-T approved without REMS due to favorable safety profile.

BCMA CAR-T (multiple myeloma)

Idecabtagene vicleucel (Abecma)

— BCMA/scFv/4-1BB-CD3ζ
FDA Mar 26, 2021 R/R MM after ≥4 prior LOT (KarMMa); FDA Apr 4, 2024 expanded to earlier line for R/R MM ≥2 prior LOT incl IMiD/PI/CD38 (KarMMa-3 — Rodriguez-Otero NEJM 2023; PFS 13.3 vs 4.4 mo, HR 0.49).

Ciltacabtagene autoleucel (Carvykti)

— BCMA/tandem dual VHH binder/4-1BB-CD3ζ
FDA Feb 28, 2022 R/R MM after ≥4 prior LOT (CARTITUDE-1); FDA Apr 5, 2024 expanded to earlier line for R/R MM ≥1 prior LOT incl PI + IMiD and lenalidomide-refractory (CARTITUDE-4 — San-Miguel NEJM 2023; PFS NR vs 11.8 mo, HR 0.26). Long-term CARTITUDE-4 (ASH 2024): potential cure fraction in standard-risk pts. Boxed warning for cilta-cel: parkinsonism and Guillain-Barré syndrome (movement and neurocognitive toxicity, distinct from ICANS; parkinsonism also reported with ide-cel); cranial nerve palsies are an additional cilta-cel warning.

Other adoptive cellular therapies (non-CAR)

Tabelecleucel (Ebvallo)

— allogeneic off-the-shelf EBV-specific cytotoxic T-lymphocytes
EU (EMA) approval Dec 2022 for EBV+ R/R PTLD post-SOT or allo-HSCT after rituximab ± chemo failure (ALLELE, Mahadeo Lancet Oncol 2024). Not FDA-approved as of Sep 2026. First approved allogeneic T-cell therapy (EU).

Lifileucel (Amtagvi)

— autologous tumor-infiltrating lymphocytes (TIL)

FDA Feb 16, 2024

for advanced melanoma post anti-PD-1 and, if BRAF V600-mut, a BRAF inhibitor +/- MEK inhibitor (C-144-01 — Chesney JITC 2022; ORR 31%). Process: tumor harvest → TIL expansion → preconditioning chemo (cyclophosphamide + fludarabine) → TIL infusion → IL-2 boluses. First T-cell (TIL) therapy approved for a solid tumor (sipuleucel-T, 2010, was an earlier cellular immunotherapy).

Afamitresgene autoleucel (Tecelra, afami-cel)

— autologous TCR-engineered T-cells targeting MAGE-A4

FDA Aug 2, 2024

for advanced/metastatic synovial sarcoma after prior chemo, MAGE-A4+ and HLA-A*02:01/02/03/06+ (SPEARHEAD-1 — D'Angelo Lancet 2024; ORR 43%, mDOR 6 mo). First engineered TCR-T for any solid tumor.

Toxicities (class)

Cytokine release syndrome (CRS) — ASTCT 2019 grading 1-4. Tx: tocilizumab (anti-IL-6R) for ≥G2 or persistent G1; steroids for refractory; anakinra (anti-IL-1) emerging. CD28 constructs → faster, higher-grade CRS.
Immune effector cell-associated neurotoxicity syndrome (ICANS) — ASTCT 2019 grading. Tx: high-dose steroids first-line (NOT tocilizumab; doesn't cross BBB). Anakinra for refractory.
Prolonged cytopenias: persistent >30 days; can require G-CSF, transfusions, eltrombopag.
Hypogammaglobulinemia / B-cell aplasia (CD19): IVIG support; PJP/HSV/VZV ppx.
HLH / macrophage activation syndrome: rare but severe; consider when CRS doesn't respond as expected.
Movement & neurocognitive toxicity (MNT): especially cilta-cel, not exclusive (Grade 3 parkinsonism also reported with ide-cel) — parkinsonism, cranial nerve palsies; distinct from ICANS, often delayed (weeks-months).
FDA Class Black Box (Jan 22, 2024): secondary T-cell malignancies — rare but serious; lifetime monitoring. Class effect for ALL CAR-T products (lentiviral and retroviral).
Infections: opportunistic during prolonged B-cell aplasia / hypogammaglobulinemia.

High-yield CAR-T pearls

CD28 construct (axi-cel, brexu-cel) = faster onset, higher CRS/ICANS, ?less persistence.
4-1BB construct (tisa-cel, liso-cel, ide-cel, cilta-cel, obe-cel) = slower, more durable, less acute toxicity.
Lymphodepletion = flu/cy for most; tisa-cel allows bendamustine (specified pts) or omission if WBC <1 x 10^9/L.
Tocilizumab for CRS; steroids for ICANS (high-dose dex; methylprednisolone for severe).
Obe-cel (Aucatzyl, Nov 2024): first CAR-T without REMS due to favorable safety.
REMS eliminated (FDA Jun 26, 2025) for all other autologous CAR-Ts (Abecma, Breyanzi, Carvykti, Kymriah, Tecartus, Yescarta); safety monitoring now via labeling.
Cilta-cel MNT: parkinsonism + cranial nerve palsies — distinct from ICANS.
2024 black box: secondary T-cell malignancies for entire class.
Lifileucel (Feb 2024): first T-cell (TIL) therapy for solid tumor (melanoma).
Afami-cel (Aug 2024): first engineered TCR-T for solid tumor (synovial sarcoma).

Summarized by Veli Bakalov, MD

References

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