Module 4

CAR-T & Cell Therapies

Chimeric antigen receptor T-cell (CAR-T) therapy engineers a patient’s own T cells to express a synthetic receptor targeting a tumour antigen. Kymriah (tisagenlecleucel, CD19, 2017) was the first FDA approval. Second- and third-generation CARs add co-stimulatory domains; TRUCK and gated variants add logic. This module covers design principles and the autoimmune/CRS toxicity profile.

1. CAR Architecture

A CAR has four components: (a) antigen-binding scFv, (b) hinge/transmembrane domain, (c) one or more co-stimulatory domains (CD28, 4-1BB, OX40), (d) CD3ζ signalling domain. First-generation CARs had only CD3ζ; second-generation added CD28 or 4-1BB; third-generation has both; fourth-generation (TRUCKs) adds a payload gene (IL-12, IL-15) for tumour-microenvironment modification.

2. Approved CAR-T Products

Kymriah (tisa-cel) — CD19, B-ALL (2017) + DLBCL (2018). 4-1BB co-stim.
Yescarta (axi-cel) — CD19, DLBCL (2017). CD28 co-stim.
Tecartus (brexu-cel) — CD19, mantle-cell lymphoma (2020).
Breyanzi (liso-cel) — CD19, DLBCL (2021).
Abecma (ide-cel) — BCMA, multiple myeloma (2021).
Carvykti (cilta-cel) — BCMA, multiple myeloma (2022).

Simulation: CAR-T Dynamics

Python

script.py38 lines

import numpy as np, matplotlib
matplotlib.use('Agg')
import matplotlib.pyplot as plt

# CAR-T persistence and tumour burden dynamics (stylised)
t = np.linspace(0, 365, 600)
# Tumour burden: rapid drop after infusion, possible relapse if CAR-T lost
tumour = 100 * np.exp(-t/10)
tumour[t > 150] += 5 * np.exp((t[t > 150] - 150)/40)
tumour[t > 250] += 60 * np.exp((t[t > 250] - 250)/30)
tumour = np.clip(tumour, 0.01, 100)

# CAR-T expansion + contraction
cart = 200 * np.exp(-(t - 14)**2 / 400) + 5 * np.exp(-t/100)

fig, (ax1, ax2) = plt.subplots(2, 1, figsize=(11, 8), facecolor='#0a0a1a')
for ax in (ax1, ax2):
    ax.set_facecolor('#111827'); ax.tick_params(colors='#cbd5e1')
    for s in ax.spines.values(): s.set_color('#334155')
    ax.grid(True, color='#334155', alpha=0.3)

ax1.semilogy(t, tumour, color='#dc2626', lw=2.5)
ax1.set_ylabel('Tumour burden (% baseline)', color='#cbd5e1')
ax1.set_title('Post-infusion tumour response and late relapse',
              color='#5eead4', fontweight='bold')

ax2.plot(t, cart, color='#2dd4bf', lw=2.5)
ax2.axvline(14, color='#fbbf24', ls='--', label='Peak expansion day ~14')
ax2.set_xlabel('Days post-infusion', color='#cbd5e1')
ax2.set_ylabel('CAR-T cells/uL', color='#cbd5e1')
ax2.set_title('CAR-T expansion/contraction',
              color='#5eead4', fontweight='bold')
ax2.legend(facecolor='#1e293b', edgecolor='#334155', labelcolor='#cbd5e1')

plt.tight_layout()
plt.savefig('output.png', dpi=120, bbox_inches='tight', facecolor='#0a0a1a')
print('Maude 2018 Kymriah: 81% CR at 3 months in pediatric B-ALL')
print('Late relapse is common: antigen escape (CD19-) or CAR-T loss')

Click Run to execute the Python code

Code will be executed with Python 3 on the server

3. Toxicities

Cytokine release syndrome (CRS): massive IL-6 surge from activated T-cells and bystander macrophages; managed with tocilizumab (anti-IL-6R) and steroids. ICANS(immune effector cell-associated neurotoxicity syndrome): confusion, seizures, cerebral edema; managed with steroids, levetiracetam. Both are reversible in most patients but require tertiary-care ICU capability during peak expansion (days 3–14).

4. Next-Generation Designs

Gated CARs use AND/NOT logic to reduce on-target off-tumour toxicity (Fedorov 2013 synNotch). Allogeneic CARs (off-the-shelf) use CRISPR-edited donor cells (Allogene, Caribou). NK and iPSC-derived CAR therapies avoid GvHD. TCR-T therapies target intracellular antigens via HLA-peptide (Adaptimmune afami-cel approved 2024 for synovial sarcoma). CAR-macrophage and in-vivo CAR mRNA-LNP approaches are emerging (Rurik 2022).

Key References

• Maude, S. L. et al. (2018). “Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia.” N. Engl. J. Med., 378, 439–448.

• Neelapu, S. S. et al. (2017). “Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma.” N. Engl. J. Med., 377, 2531–2544.

• June, C. H. & Sadelain, M. (2018). “Chimeric antigen receptor therapy.” N. Engl. J. Med., 379, 64–73.

• Rurik, J. G. et al. (2022). “CAR T cells produced in vivo to treat cardiac injury.” Science, 375, 91–96.

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