Teaching pack: Immunotherapy

Checkpoint inhibitors (PD-1, PD-L1, CTLA-4, LAG-3), bispecific T-cell engagers, cancer vaccines (including personalised mRNA neoantigen vaccines), oncolytic viruses, cytokines, and innate-immune agonists. Determining who responds, and converting cold tumours to hot, are the central problems.

• Antibody manufacturing (CHO bioprocessing): Antibody manufacturing means growing antibody drugs like pembrolizumab or trastuzumab in vats of engineered hamster cells, then purifying them. It is the industrial base for most modern cancer drugs.
• Bacteriophage-based tumour delivery: Using viruses that infect bacteria, not human cells, as programmable delivery shells for cancer drugs and vaccines.
• Bispecific antibodies: A bispecific antibody is one antibody with two different grabbing arms, so it can block two targets at once or pull an immune cell onto a cancer cell.
• Cancer interception vaccines: Vaccinating people who do not have cancer yet but are very likely to get it, against the antigens their future tumour will carry.
• 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.
• Chronotherapy: timing treatment to the body clock: Giving the same drug at a different time of day, because the body clock changes how much damage it does and how well the immune system responds.
• Cytokines & engineered cytokines: Cytokine therapy gives immune-signalling proteins as drugs. High-dose interleukin-2 was the first immunotherapy to cure some melanomas, at great toxicity.
• Dietary fibre and the gut microbiome for immunotherapy response: Patients who eat plenty of fibre and avoid probiotic pills seem to respond better to immunotherapy for melanoma, probably because fibre feeds the right gut bacteria. A proper trial is under way.
• Engineered bacteria as living cancer drugs: Bacteria that seek out the low-oxygen core of tumours, then manufacture a drug on the spot.
• Faecal microbiota transplantation for PD-1 non-responders: Transplanting gut bacteria from patients who responded to immunotherapy into those who did not. In small studies a minority of resistant melanomas started responding. Randomised trials are running.

• Immunotherapy roadmap: Coley's toxins → checkpoint inhibitors → engineered immunity · Prehistory (historic)
• Immunotherapy roadmap: Coley's toxins → checkpoint inhibitors → engineered immunity · Checkpoint revolution (historic)
• Immunotherapy roadmap: Coley's toxins → checkpoint inhibitors → engineered immunity · Earlier lines and combinations (current)
• Immunotherapy roadmap: Coley's toxins → checkpoint inhibitors → engineered immunity · Engineered immunity arrives (emerging)
• Immunotherapy roadmap: Coley's toxins → checkpoint inhibitors → engineered immunity · Speculative (speculative)

• KEYNOTE-006 (phase 3, n=834): Overall survival at 10 years: 34% vs 23.6%
• IMpower133 (phase 3, n=403): Overall survival: 12.3 months vs 10.3 months, HR 0.7
• ECOG-ACRIN E1910 (phase 3, n=488): Overall survival at 3 years (MRD-negative cohort): 85% vs 68%, HR 0.41
• IMCgp100-202 (phase 3, n=378): Overall survival: 21.7 months vs 16 months, HR 0.51
• TOWER (phase 3, n=405): Overall survival (median): 7.7 months vs 4 months, HR 0.71
• COG AALL1731 (phase 3, n=1,440): Disease-free survival at 3 years: 96% vs 87.9%, HR 0.39

1. What was the first personalised cancer vaccine to win a phase 3 trial?
   Answer

   Intismeran autogene (V940/mRNA-4157, Moderna/Merck) with pembrolizumab in resected stage IIB-IV melanoma: INTerpath-001 met recurrence-free and distant-metastasis-free survival, announced 19 August 2026.
2. How is a personalised mRNA cancer vaccine made?
   Answer

   The tumour and normal DNA are sequenced, software predicts up to 34 neoantigens unique to the tumour, a patient-specific mRNA encoding them is manufactured in lipid nanoparticles over about six weeks, and it is given with a PD-1 blocker.
3. What are the main side effects of checkpoint inhibitors and how are they handled?
   Answer

   Immune-related adverse events such as colitis, thyroid problems, rash, hepatitis, and pneumonitis, most common with CTLA-4 plus PD-1 combinations; treated with steroids and sometimes other immunosuppressants, some endocrine effects are permanent.
4. Name three next-generation ADC concepts beyond bispecific antibodies.
   Answer

   Dual-payload ADCs, degrader-antibody conjugates, immune-stimulating antibody conjugates, masked or conditionally active ADCs, peptide-drug conjugates, radio-ADCs.
5. Why might personalised vaccines work better after surgery than in metastatic disease?
   Answer

   Tumour burden is low so immune responses are not overwhelmed, there is time for the six-week manufacturing, immunosuppression from bulky disease is absent, and recurrence-free survival is a clean endpoint; INTerpath-001 tested exactly this adjuvant setting.