What is the role of immunotherapy in cancer treatment?

Immunotherapy in Cancer Treatment

Immunotherapy has become a cornerstone of modern cancer treatment, offering durable survival benefits across multiple cancer types through immune checkpoint inhibitors, adoptive cell therapies, and other immune-modulating approaches that activate the body's anti-tumor immune response.

Core Immunotherapy Modalities

Immunotherapy encompasses several distinct therapeutic approaches that manipulate the immune system to recognize and destroy cancer cells 1:

• Immune checkpoint inhibitors (anti-PD-1, anti-PD-L1, anti-CTLA-4) block inhibitory signals that prevent T-cell activation, releasing the brake on anti-tumor immunity 1, 2
• Adoptive cell therapies including CAR-T cells that are engineered to express chimeric antigen receptors targeting tumor neoantigens 3
• Cytokines such as high-dose interleukin-2 and interferon-α that directly stimulate immune responses 1
• Cancer vaccines and oncolytic viruses that enhance tumor antigen presentation 1, 3
• Monoclonal antibodies that target tumor-specific antigens or block angiogenesis 4

Disease-Specific Applications

Head and Neck Squamous Cell Carcinoma

For recurrent or metastatic HNSCC with PD-L1 CPS ≥1, pembrolizumab monotherapy or pembrolizumab plus platinum and fluorouracil should be offered as first-line treatment 1. This recommendation is based on high-quality evidence demonstrating survival benefits.

• PD-L1 combined positive score (CPS) ≥1 correlates with clinical benefit to PD-1 inhibitors and should be interpreted as positive 1
• For patients with CPS <1, pembrolizumab plus platinum and fluorouracil may still be offered based on moderate-quality evidence 1
• Tumor mutational burden (TMB) ≥10 should be interpreted as high and correlates with benefit when CPS is unavailable 1

Nasopharyngeal Carcinoma (Virus-Associated)

Toripalimab, camrelizumab, or tislelizumab combined with gemcitabine and cisplatin should be offered as first-line treatment for recurrent or metastatic nasopharyngeal cancer 1. This EBV-driven malignancy demonstrates meaningful clinical benefit from immunotherapy regardless of PD-L1 status 5.

• Nivolumab achieved 21% objective response rate with 59% one-year overall survival in recurrent/metastatic disease 5
• Treatment-related adverse events are substantially lower with immunotherapy (61.2%) compared to chemotherapy (87.5%), with grade 3-5 toxicity only 10.3% versus 43.8% 5

Melanoma

Anti-PD-1 monotherapy (pembrolizumab or nivolumab) is the preferred first-line treatment for unresectable or metastatic melanoma due to durable long-term survival benefits 6, 5. No biomarker selection is required for anti-PD-1 monotherapy in the metastatic setting 6, 5.

• Combination ipilimumab/nivolumab can be used for patients who can tolerate increased toxicity 6, 5
• Adjuvant nivolumab or pembrolizumab is indicated for completely resected Stage IIB, IIC, Stage III, or Stage IV melanoma to reduce recurrence risk 6
• Extended follow-up of ipilimumab showed 5-year overall survival of 18% versus 9% for dacarbazine, demonstrating long-term benefit in approximately 20% of patients 5

Bladder Cancer

Intravesical BCG remains the standard of care for non-muscle-invasive bladder cancer, activating the immune system to recognize and destroy malignant cells with demonstrated durable clinical benefit 1.

• Immune checkpoint inhibitors are approved for platinum-resistant or platinum-ineligible metastatic bladder cancer 1
• Considerations for expanded use in both advanced and potentially localized disease are ongoing 1

Biomarker-Guided Treatment Selection

When Biomarkers Are Required

• BRAF mutation testing should be performed for Stage III-IV melanoma to determine eligibility for targeted therapy alternatives, though immunotherapy remains preferred first-line in most cases 6
• PD-L1 testing guides treatment selection in HNSCC, with CPS ≥1 predicting benefit from pembrolizumab monotherapy 1

When Biomarkers Are Not Required

• Melanoma does not require biomarker selection for anti-PD-1 monotherapy in the metastatic setting 6, 5
• Virus-associated cancers often show responses independent of PD-L1 status, with similar response rates in PD-L1-positive and PD-L1-negative patients (27.1% vs 19.1%, P=0.31) 5

Mechanism of Action

Atezolizumab and other PD-L1 inhibitors bind to PD-L1 and block its interactions with both PD-1 and B7.1 receptors, releasing PD-L1/PD-1 mediated inhibition of the immune response and activating anti-tumor immunity without inducing antibody-dependent cellular cytotoxicity 2. Anti-CTLA-4 antibodies block binding between CTLA-4 receptors and B7 ligands, preventing inhibition of activated cytotoxic T cells 4.

Response Assessment and Timing

Do not use traditional RECIST criteria alone to assess response; immune-related response criteria should be employed as tumor regression may occur over prolonged periods 1, 6. This is critical because immunotherapy requires time to establish an effective host anti-tumor immune response 1.

• Steady-state drug levels are achieved after 6 to 9 weeks with checkpoint inhibitors 2
• Do not discontinue therapy prematurely for apparent progression without considering pseudoprogression 6
• Only a subset of patients respond, but therapeutic benefits can be durable 1

Toxicity Management

Be prepared to manage immune-related adverse events aggressively, as these can affect any organ system and may require corticosteroids or other immunosuppression 6. Unique adverse effects relate to induction of autoimmunity and pro-inflammatory states 1.

Contraindications

• Patients with active autoimmune disease requiring systemic immunosuppression represent a relative contraindication 6
• Adequate performance status is required to tolerate immune-related adverse events and sufficient organ function to manage potential immune-mediated toxicities 6

Critical Clinical Pitfalls to Avoid

Do not delay immunotherapy initiation while waiting for molecular testing results in clearly metastatic disease, as checkpoint inhibitors do not require mutation-specific selection 6. This is particularly important in melanoma where anti-PD-1 therapy should begin promptly.

• Many patients with bladder cancer do not receive appropriate BCG therapy despite established guidelines 1
• Immune-related response criteria must be used instead of traditional RECIST criteria to avoid premature treatment discontinuation 1, 6
• Treatment-related adverse events require vigilant monitoring and aggressive management with immunosuppression when indicated 6

Emerging Directions

Recent advances include CAR-T cell therapy for hematological cancers, combination strategies with targeted therapies, and novel immune checkpoint targets beyond PD-1/PD-L1 and CTLA-4 7, 3. Comprehensive profiling of tumor-infiltrating immune cells using single-cell technologies is providing insights into mechanisms of cancer-immune evasion and guiding development of novel therapeutic strategies 8.