History and Overview of Cancer Immunotherapy

1. Historical Milestones

| Year | Milestone | Significance |
|——|———–|————–|
| 1890s | William Coley uses mixed bacterial toxins (Coley’s toxins) | First deliberate immune stimulation causing tumor regression |
| 1950s–1970s | Concepts of tumor immunosurveillance; identification of tumor antigens | Foundation for adaptive immune targeting |
| 1980s–1990s | Development of hybridoma technology; clinical monoclonal antibodies (e.g., rituximab) | Launch of therapeutic mAb era |
| 1990s | Discovery of CTLA‑4 and PD‑1 as inhibitory receptors | Established immune checkpoint paradigm |
| 2000s | Checkpoint antibody clinical breakthroughs (ipilimumab, anti–PD‑1/PD‑L1) | Durable responses in melanoma and beyond |
| 2010s | CAR‑T approvals (CD19), expansion across solid tumor trials | Proof of concept for engineered cellular therapy |
| 2018 | Nobel Prize to Allison & Honjo (CTLA‑4, PD‑1) | Validation of immune checkpoint blockade impact |
| 2020s | Multi‑specific antibodies, bispecific T‑cell engagers, next‑gen cell therapies | Diversification of immune platforms |

2. Conceptual Framework

Traditional cytotoxics and targeted small molecules directly injure or inhibit tumor cell pathways. Immunotherapy instead amplifies or reprograms host immune mechanisms to recognize and eliminate malignant cells, aiming for durable immunologic memory.

Immune Editing Phases

1. Elimination (immune recognition & destruction)
2. Equilibrium (tumor persistence under immune pressure)
3. Escape (selection of less immunogenic variants)

3. Classification Approaches

There is no single universal classification; two pragmatic lenses are commonly used.

A. By Immune Engagement Mode

| Category | Mechanism | Examples |
|———-|———-|———-|
| Passive | Provides ready‑made immune effectors | Monoclonal antibodies, cytokines (IFN‑α, IL‑2), adoptive T cells |
| Active | Induces or primes endogenous immunity | Vaccines (peptide, dendritic cell), oncolytic viruses |

B. By Technology Platform

| Platform | Core Principle | Representative Therapies |
|———-|—————-|————————–|
| Monoclonal antibodies | Target tumor or immune checkpoints | Trastuzumab, Pembrolizumab, Nivolumab |
| Checkpoint inhibitors | Block inhibitory receptor–ligand axes | CTLA‑4, PD‑1, PD‑L1 antibodies |
| Cellular therapies | Genetic or ex vivo activation of immune cells | CAR‑T (CD19, BCMA), TCR‑T, TIL therapy |
| Bispecific antibodies / T‑cell engagers | Bridge T cells to tumor antigens | Blinatumomab (CD19×CD3), Teclistamab (BCMA×CD3) |
| Vaccines | Present tumor antigens to prime T cells | Sipuleucel‑T, neoantigen vaccines (trial) |
| Oncolytic viruses | Selective tumor infection & immune priming | T‑VEC (HSV‑1) |
| Cytokine therapies | Systemic or engineered immune stimulation | High‑dose IL‑2, pegylated IL‑2 variants |
| Innate immune modulators | Activate macrophage/DC pathways | CD47 blockers, STING agonists (investigational) |

4. PD‑1 / PD‑L1 Axis Explained

• PD‑1: Inhibitory receptor on activated T and B cells; limits effector function to maintain tolerance.
• Ligands: PD‑L1 (broad expression on tumor & myeloid cells), PD‑L2 (restricted to APCs).
• Tumor Immune Evasion: Upregulated PD‑L1 binds PD‑1 → decreased proliferation, cytokine secretion, cytotoxicity.
• Therapeutic Antibodies: Block PD‑1 (e.g., nivolumab, pembrolizumab) or PD‑L1 (e.g., atezolizumab, durvalumab) to restore T‑cell activity.

PD‑L1 Expression Nuances

| Expression Category | Approximate Threshold (TPS / CPS) | Typical Clinical Interpretation |
|———————|————————————|——————————–|
| High | ≥50% (some indications ≥ CPS 10) | Greater probability of response to monotherapy |
| Intermediate | 1–49% | Benefit; combination strategies often favored |
| Negative | <1% | Lower monotherapy response; chemo‑immunotherapy or alternate strategies |

Heterogeneity: Different metastatic sites may show discordant PD‑L1 levels due to clonal evolution and microenvironmental pressures.

5. Treatment Modalities & Combinations

| Strategy | Rationale | Illustrative Use |
|———-|———-|——————|
| ICI monotherapy | Favorable biomarker (high PD‑L1, MSI‑H, high TMB) | First‑line metastatic NSCLC (PD‑L1 ≥50%) |
| Dual checkpoint blockade | Synergistic T‑cell priming + effector reinvigoration | CTLA‑4 + PD‑1 in melanoma |
| Chemo‑immunotherapy | Cytotoxic debulking increases antigen release | NSCLC non‑squamous regimens |
| Radiation + ICI | Abscopal priming; inflames “cold” tumor | Oligometastatic disease trials |
| Targeted + ICI | Pathway inhibition may modulate immune milieu | BRAF/MEK + anti‑PD‑1 in melanoma |
| Anti‑angiogenic + ICI | Vascular normalization improves infiltration | HCC: Atezolizumab + Bevacizumab |

6. Biomarkers Beyond PD‑L1

| Biomarker | Mechanistic Basis | Clinical Utility |
|———-|——————|——————|
| MSI‑H / dMMR | High neoantigen burden | Pan-tumor indication for PD‑1 blockade |
| TMB (high) | Increased mutational neoepitopes | Predicts response probability (context dependent) |
| Gene expression signatures (IFN‑γ) | Pre‑existing immune activation | May enrich ICI responders |
| Lymphocyte infiltration (TIL density) | Pre‑existing immunity | Prognostic; predictive in some tumors |
| POLE/POLD1 mutations | Hypermutated phenotype | Elevated ICI sensitivity |
| ctDNA dynamics | Early on‑treatment molecular response | Treatment adaptation |

7. Mechanisms of Primary & Acquired Resistance

| Category | Examples |
|———-|———-|
| Antigen presentation loss | B2M mutations, MHC downregulation |
| Interferon signaling defects | JAK1/2 loss-of-function |
| Immunosuppressive microenvironment | Tregs, MDSCs, adenosine, IDO pathway |
| Alternative checkpoints | LAG‑3, TIGIT, TIM‑3 upregulation |
| Metabolic barriers | Hypoxia, lactate accumulation |

8. Safety & Toxicity (Immune‑Related Adverse Events, irAEs)

| Organ System | Common Manifestations | Management Principles |
|————–|———————-|———————-|
| Dermatologic | Rash, pruritus, vitiligo | Topical steroids; continue unless severe |
| GI | Diarrhea, colitis | Grade-based steroids; infliximab/vedolizumab if refractory |
| Hepatic | AST/ALT elevation | Rule out other causes; steroids; mycophenolate for steroid-refractory |
| Endocrine | Hypothyroid, hyperthyroid, hypophysitis, adrenal insufficiency | Hormone replacement (usually lifelong); rarely discontinue |
| Pulmonary | Pneumonitis | Hold drug; steroids; taper ≥4–6 weeks |
| Musculoskeletal | Arthralgia, inflammatory arthritis | NSAIDs → low-dose steroids; rheumatology input |
| Neurologic | Neuropathy, myasthenia-like syndrome | Urgent evaluation; high-dose steroids; IVIG/PLEX |
| Cardiac | Myocarditis | High-dose steroids early; cardiology consult |

9. Role in Neuroendocrine Tumors (NETs)

• Overall response rates to single-agent PD‑1/PD‑L1 blockade in unselected well-differentiated NETs are low.
• Consider only after progression on standard therapies and in presence of predictive biomarkers (MSI‑H, dMMR, high TMB, occasionally high PD‑L1 in aggressive phenotypes).
• Combination strategies and microenvironment modulation are under active investigation.

10. Future Directions

• Multi‑checkpoint combinations (PD‑1 + LAG‑3/TIGIT) to overcome adaptive resistance.
• Personalized neoantigen vaccines + checkpoint blockade.
• Bispecific and trispecific constructs integrating costimulation.
• Oncolytic virus + ICI for immune desert tumors.
• Spatial transcriptomics and radiomics to refine patient selection.

11. Practical Clinical Pearls

• Always confirm biomarker status (PD‑L1, MSI/MMR, TMB) before selecting ICI monotherapy where alternatives exist.
• Monitor early for subtle irAEs; patient education improves prompt reporting.
• Re-biopsy or liquid biopsy at progression can reveal resistance pathways guiding trial enrollment.
• Assess inter-lesional heterogeneity when interpreting mixed responses.

12. Key Takeaways

• Immunotherapy has transitioned from empirical stimulation to precise modulation of immune checkpoints and cellular effectors.
• PD‑1/PD‑L1 blockade efficacy varies by biomarker profile, tumor type, and microenvironmental context.
• Resistance involves antigen presentation defects, suppressive cell populations, and alternative inhibitory receptors.
• Rational combinations and next‑generation engineering aim to convert non‑inflamed (“cold”) tumors to immune‑responsive states.

Disclaimer: Educational overview; not a substitute for individualized medical judgment.