Here is a thorough general overview of cancer immunotherapy, drawn from Goodman & Gilman's Pharmacological Basis of Therapeutics, Roitt's Essential Immunology, and Sabiston's Textbook of Surgery:
Cancer Immunotherapy - General Overview
What Is It?
Immunotherapy uses the patient's own immune system to recognize and destroy cancer cells. Cancer cells express abnormal proteins (tumor-associated antigens) that should trigger an immune response - but tumors have evolved clever ways to evade this surveillance. Immunotherapy works by overcoming those evasion strategies.
Key principle: Immunotherapy works best when the tumor burden has already been reduced by surgery, radiation, or chemotherapy. The immune system cannot be expected to eliminate a large tumor mass on its own.
The 6 Main Types of Cancer Immunotherapy
1. Immune Checkpoint Inhibitors (ICIs) - Most Widely Used
Cancer cells "put the brakes" on T cells by expressing inhibitory molecules. ICIs remove those brakes.
The two main checkpoint pathways targeted are:
| Checkpoint | What It Does | How Cancer Exploits It |
|---|
| CTLA-4 | Competes with CD28 for B7 binding, dampening T-cell activation | Upregulated on T cells in the tumor environment |
| PD-1 / PD-L1 | PD-1 on T cells binds PD-L1 on tumor cells, inducing T-cell "exhaustion" | Tumor cells overexpress PD-L1 to hide from T cells |
Immune checkpoint evasion and the antibodies that block them - Goodman & Gilman's
Approved checkpoint inhibitors include:
- Anti-PD-1: Pembrolizumab (Keytruda), Nivolumab (Opdivo)
- Anti-PD-L1: Atezolizumab, Durvalumab, Avelumab
- Anti-CTLA-4: Ipilimumab (Yervoy)
Cancers approved for ICI therapy (FDA-approved): Melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma, head and neck cancers, bladder cancer, Hodgkin lymphoma, gastric cancer, hepatocellular carcinoma, colorectal cancer (MSI-high), Merkel cell carcinoma, and others.
James Allison (anti-CTLA-4) and Tasuku Honjo (anti-PD-1) shared the 2018 Nobel Prize in Physiology/Medicine for this discovery.
2. Passive Immunotherapy - Monoclonal Antibodies (mAbs)
Humanized antibodies are designed to directly target proteins overexpressed on tumor cells:
| Antibody | Target | Cancer |
|---|
| Trastuzumab (Herceptin) | HER2 | Breast, gastric cancer |
| Rituximab | CD20 | B-cell lymphoma |
| Cetuximab | EGFR | Colorectal, head & neck |
| Bevacizumab | VEGF-A | Multiple cancers (anti-angiogenic) |
| Alemtuzumab | CD52 | CLL |
These antibodies work by:
- Blocking growth factor receptors (preventing tumor proliferation signals)
- Enabling NK cell-mediated ADCC (antibody-dependent cellular cytotoxicity)
- Activating complement
3. CAR-T Cell Therapy (Chimeric Antigen Receptor T Cells)
A patient's own T cells are collected, genetically engineered in the lab to express a synthetic receptor (CAR) that targets a specific tumor antigen, expanded massively, then infused back into the patient.
- CD19 CAR-T (e.g., Axicabtagene, Tisagenlecleucel) - used in B-cell leukemias/lymphomas (CLL, ALL, DLBCL)
- BCMA CAR-T - used in multiple myeloma
- These can produce highly durable responses in previously untreatable disease
4. Cancer Vaccines
- Prophylactic vaccines: HPV vaccine (Gardasil) prevents cervical cancer; HBV vaccine prevents hepatocellular carcinoma
- Therapeutic vaccines: Designed to stimulate immune responses against existing tumor antigens (e.g., sipuleucel-T for prostate cancer)
- Most effective against virally-induced cancers
5. Cytokine Therapy
Cytokines directly boost the immune response:
- IL-2 (Interleukin-2): High-dose IL-2 can produce durable responses in metastatic melanoma and renal cell carcinoma
- Interferons (IFN-alpha/gamma/beta): Used in hairy cell leukemia, mycosis fungoides, Kaposi's sarcoma, and some lymphomas
- GM-CSF: Enhances anti-tumor immunity
6. Antibody-Drug Conjugates (ADCs) & Other Targeted Biologics
- Monoclonal antibodies are linked to chemotherapy toxins or radiolabels, delivering a "guided missile" directly to tumor cells
- Examples: Trastuzumab emtansine (T-DM1), Brentuximab vedotin (anti-CD30)
- Bispecific antibodies (e.g., Blinatumomab) that bring T cells into proximity with tumor cells
Key Biomarkers Used to Select Patients for Immunotherapy
| Biomarker | Test | Significance |
|---|
| PD-L1 expression | IHC on biopsy | Higher PD-L1 = better response to PD-1/PD-L1 blockers |
| TMB (Tumor Mutational Burden) | Genomic sequencing | High TMB = more neoantigens = better ICI response |
| MSI-H / dMMR | PCR or IHC | Mismatch repair deficiency = good response to pembrolizumab |
| HER2 amplification | FISH / IHC | Target for trastuzumab |
| CD20 expression | IHC | Target for rituximab |
Side Effects (Immune-Related Adverse Events / irAEs)
Because ICIs release the immune system's brakes, they can cause the immune system to attack normal tissues:
- Skin: Rash, vitiligo, pruritus
- Gut: Colitis, diarrhea
- Lung: Pneumonitis
- Liver: Hepatitis (transaminase elevation)
- Endocrine: Thyroiditis, hypophysitis, adrenal insufficiency, type 1 diabetes
- Joints: Arthritis, myositis
Management involves holding the immunotherapy and treating with corticosteroids (and sometimes other immunosuppressants for severe cases).
Summary Table
| Type | Example Drugs | Mechanism |
|---|
| Checkpoint inhibitors | Pembrolizumab, Nivolumab, Ipilimumab | Release T-cell brakes |
| Monoclonal antibodies | Trastuzumab, Rituximab, Bevacizumab | Direct tumor targeting, ADCC |
| CAR-T cells | Axicabtagene, Tisagenlecleucel | Engineered T cells attack tumor |
| Cancer vaccines | HPV vaccine, Sipuleucel-T | Prime immune response to tumor antigens |
| Cytokines | IL-2, IFN-alpha | Boost immune system activity |
| ADCs | T-DM1, Brentuximab | Guided chemo delivery |
Sources: Goodman & Gilman's Pharmacological Basis of Therapeutics; Roitt's Essential Immunology; Sabiston Textbook of Surgery
Would you like me to go deeper into any specific type - for example, checkpoint inhibitors for a particular cancer, CAR-T therapy, or the side effects and their management?