Teaching pack: Cell Therapy

CAR-T has transformed B-cell malignancies and myeloma. Solid tumours are the frontier: TIL therapy (lifileucel), TCR-T (afamitresgene), CAR-T against CLDN18.2 and GPC3, armoured and logic-gated CARs, allogeneic and in vivo CAR-T (targeted LNPs delivering CAR mRNA), CAR-NK and CAR-macrophages.

• Allogeneic (off-the-shelf) cell therapy: Cell therapies made from healthy donors in advance, so patients do not have to wait for their own cells to be engineered.
• Allogeneic donor and iPSC master cell banks: Making cell therapies from a healthy donor or stem-cell line in advance, so patients get an off-the-shelf product instead of waiting weeks.
• Allogeneic stem cell transplantation: Replacing a patient's blood system with a donor's, so the donor's immune cells hunt down any leukaemia left behind. Still the only cure for many high-risk leukaemias.
• Apheresis and starting-material collection: Apheresis is collecting a patient's white blood cells through a machine over several hours. Every autologous CAR-T begins here, and the quality of these cells shapes the final product.
• Armoured, logic-gated & next-gen CARs: Upgraded CAR-T cells that also secrete immune boosters, resist exhaustion, or only fire when two signals are present.
• Autologous stem cell transplant (high-dose therapy): Collect the patient's own blood-forming stem cells, give a very high dose of chemotherapy that would otherwise destroy the marrow, then give the cells back to rebuild it.
• CAR-NK & CAR-macrophage: Putting the cancer-seeking receptor on natural killer cells or macrophages instead of T cells, which could be safer and off-the-shelf.
• CAR-T against stroma: fibroblasts and myeloid cells: Instead of attacking the cancer cell, engineering T cells to strip away the scaffolding and the suppressive immune cells that protect it.
• CAR-T cell therapy: A patient's T cells are removed, given a synthetic receptor that recognises the cancer, multiplied, and put back as a living drug.
• CAR-T for glioma (IL13Rα2, GD2, EGFRvIII, multi-target): Engineered immune cells delivered directly into the brain or spinal fluid. Some children with an incurable brainstem tumour have had striking, if temporary, responses.

• Cell therapy roadmap: CD19 CAR-T → solid tumours → in vivo CAR · Foundations (historic)
• Cell therapy roadmap: CD19 CAR-T → solid tumours → in vivo CAR · CD19 and BCMA CAR-T approved (historic)
• Cell therapy roadmap: CD19 CAR-T → solid tumours → in vivo CAR · Solid tumours: TIL, TCR-T, CAR-T (current)
• Cell therapy roadmap: CD19 CAR-T → solid tumours → in vivo CAR · Manufacturing revolution: allogeneic and in vivo (emerging)
• Cell therapy roadmap: CD19 CAR-T → solid tumours → in vivo CAR · Speculative (speculative)
• Paths to cures: interception, eradication, control · What already prevents cancer (historic)
• Paths to cures: interception, eradication, control · Vaccinating and monitoring people who do not yet have cancer (emerging)
• Paths to cures: interception, eradication, control · Removing every cell, and knowing that you did (current)
• Paths to cures: interception, eradication, control · Killing the last cell, wherever it is hiding (emerging)
• Paths to cures: interception, eradication, control · Living with cancer as a chronic disease (current)
• Paths to cures: interception, eradication, control · Steering resistance instead of waiting for it (emerging)
• Radical oncology: what could change the war by 2035 · Ideas already being tested against a control arm (current)
• Radical oncology: what could change the war by 2035 · Living drugs, logic gates, and designed proteins reach decision points (emerging)
• Radical oncology: what could change the war by 2035 · Radiation and radiopharmaceuticals get a second act (emerging)
• Radical oncology: what could change the war by 2035 · Monitoring becomes continuous and selection becomes spatial (emerging)
• Radical oncology: what could change the war by 2035 · Writing to the genome and the epigenome inside a tumour (speculative)
• Radical oncology: what could change the war by 2035 · Treating the soil rather than the seed (speculative)

• PERSEUS (phase 3, n=709): Progression-free survival at 48 months: 84.3% vs 67.7%, HR 0.42
• ZUMA-7 (phase 3, n=359): Event-free survival (median): 8.3 months vs 2 months, HR 0.4
• CARTITUDE-4 (phase 3, n=419): Progression-free survival: pending
• TRANSFORM (phase 3, n=184): Event-free survival (median): 29.5 months vs 2.4 months, HR 0.36
• AETHERA (phase 3, n=329): Progression-free survival (median): 42.9 months vs 24.1 months, HR 0.57
• COG ANBL0532 (phase 3, n=652): Event-free survival at 3 years: 61.6% vs 48.4%

1. What is the first approved TIL therapy and how well does it work?
   Answer

   Lifileucel (Amtagvi, Iovance), approved 2024 for anti-PD-1-refractory melanoma: response rate about 31%, with roughly a third of responders still responding at five years.
2. What is CAR-T and which cancers is it approved for?
   Answer

   A patient's T cells are engineered with a synthetic receptor, multiplied, and returned. Approved CD19 products treat B-cell lymphomas and leukaemias; BCMA products treat multiple myeloma; the first solid-tumour approval (Claudin 18.2, gastric) is in China.
3. What is in vivo CAR-T and why is it exciting?
   Answer

   Targeted lipid nanoparticles or viral vectors deliver CAR-encoding mRNA or DNA to T cells inside the patient, avoiding manufacturing, lymphodepletion, and wait time and allowing redosing; first-in-human data in 2025-26 show B-cell depletion. AbbVie bought Capstan for up to $2.1B.