What is the role of immunotherapy in the treatment of various diseases, including cancers and autoimmune disorders?

Immunotherapy in Cancer and Autoimmune Disease: Evidence-Based Overview

Core Mechanism and Clinical Impact

Immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1, and CTLA-4 have revolutionized cancer treatment by blocking proteins that allow tumor cells to evade immune detection, significantly improving overall survival across multiple cancer types. 1

• ICIs work by preventing tumor cells from suppressing T-cell-mediated immune responses, restoring the body's natural ability to recognize and destroy malignant cells 2, 3
• Since FDA approval of ipilimumab in 2011, indications have expanded dramatically to include melanoma, non-small cell lung cancer, head and neck cancers, urothelial carcinoma, and numerous other malignancies 1
• These agents produce durable clinical benefit in responding patients, with some achieving long-term remission even after treatment discontinuation 1

Safety Profile and Immune-Related Adverse Events

The incidence of any-grade immune-related adverse events (irAEs) ranges from 15% to 90% depending on the specific agent and regimen, with severe events leading to treatment discontinuation in up to 13% of patients receiving anti-PD-1 monotherapy 1

Temporal Patterns of Toxicity

• Earlier-onset irAEs (weeks to months) typically involve generalized epithelial inflammation manifesting as rash, colitis, and pneumonitis 1
• Later-onset irAEs (months) tend to be more organ-specific and less common, including endocrinopathies and neurologic complications 1
• Unlike cytotoxic chemotherapy with acute emetic and myelosuppressive effects, irAEs are delayed in onset and inflammatory or autoimmune in nature 1

Combination Therapy Considerations

Combination ICI regimens offer enhanced efficacy but carry substantially greater toxicity compared to monotherapy, requiring careful patient selection and monitoring 1

Management in Special Populations

Patients with Pre-existing Autoimmune Disease

Immunotherapy is not an absolute contraindication in patients with pre-existing autoimmune disease, but requires individualized risk assessment based on disease activity and immunosuppression requirements. 1

Contraindications to Proceeding

• Currently active autoimmune disease requiring systemic immunosuppressive medication (94% expert consensus against combination therapy) 4
• Corticosteroid requirement >10 mg/day prednisone equivalent (75% of experts recommend against treatment) 5, 4
• Life-threatening autoimmune manifestations 5

Candidates for Cautious Proceeding

• Patients with controlled autoimmune disease on low-dose prednisone (≤10 mg/day) or hydroxychloroquine alone may proceed with enhanced monitoring 5, 4
• Patients with rheumatoid arthritis stable on disease-modifying agents without active systemic inflammation 5
• History of organ-specific autoimmunity with adequate substitutive treatment (e.g., hypothyroidism on levothyroxine) 4

Clinical Outcomes Data

In retrospective series of patients with advanced melanoma and autoimmune disorders, flare-ups of pre-existing disease occurred in 27%-50% of cases (10%-25% high-grade), while 25%-30% developed conventional irAEs, with most managed successfully with corticosteroids 1

Critically, objective response rates remained at 20% with ipilimumab, consistent with the general population, and 50% of patients experienced neither autoimmune flare nor high-grade irAEs 5, 6

Solid Organ Transplant Recipients

There is no absolute contraindication for solid organ transplant recipients with cancer to receive immunotherapy, but graft rejection risk must be weighed against survival benefit, particularly for renal transplant patients. 1

• Periodic monitoring of immunosuppressant drug levels and adjustment of doses is required throughout treatment 1
• If graft rejection occurs, high-dose corticosteroids or other immunosuppressive therapies are indicated, with dialysis typically required for renal transplant rejection 1
• Immunotherapy reinitiation can be considered in patients who recover after graft rejection, especially in renal transplant cases where patients can survive graft loss on dialysis 1

Pregnancy

Pregnancy during immunotherapy treatment must be avoided, but if cancer develops during pregnancy, checkpoint inhibitors are not absolutely contraindicated despite increased risk of pregnancy complications. 1

• Theoretical concerns exist regarding increased abortion and premature delivery risk due to disruption of maternal-fetal immune tolerance 1
• Three case reports documented treatment with nivolumab or combination ipilimumab/nivolumab without major obstetric complications 1
• Data on teratogenic potential in humans remain lacking 1

Allogeneic Bone Marrow Transplantation

Previous allogeneic bone marrow transplantation is not an absolute contraindication to anti-PD-1 therapy, though high risk of graft-versus-host disease exists and should be reserved for patients without other treatment options. 1

• Anti-PD-1 therapy after allogeneic transplant carries high risk of graft-versus-host disease and immune-related toxicities but may produce antitumor responses via graft-versus-lymphoma effect 1
• Allogeneic transplantation in patients previously treated with anti-PD-1 antibodies similarly carries elevated complication risk 1

Chronic Infections and Immunosuppression

HIV-1 Infection

Cancer immunotherapy in HIV-infected patients is feasible with multidisciplinary management, as life expectancy under viral suppressive combination antiretroviral therapy approaches that of non-infected persons, though chronic inflammation increases cancer risk. 1

• Cancer is now a leading cause of death in people living with HIV due to improved survival on antiretroviral therapy 1
• Treatment requires coordination between oncology and infectious disease specialists to monitor for complications 1

Viral Hepatitis and Tuberculosis

Patients with chronic viral hepatitis or latent tuberculosis require specialized monitoring but are not categorically excluded from immunotherapy, necessitating multidisciplinary collaboration 1

Critical Pitfalls to Avoid

• Do not exclude patients solely based on autoimmune diagnosis without assessing disease activity—half experience no complications and response rates remain comparable to the general population 5, 4, 6
• Baseline corticosteroids >10 mg/day during immunotherapy initiation should be avoided, as they decrease objective response rate, progression-free survival, and overall survival 5, 7
• Do not delay rheumatology consultation when musculoskeletal symptoms develop during treatment, as early intervention improves outcomes 4
• Recognize that blood in stools with fever may indicate infection or peptic ulcer disease rather than immune-mediated colitis, requiring appropriate diagnostic workup 1

Monitoring and Management Algorithm

Recognition of Immune-Related Adverse Events

Prompt recognition and intervention are essential for successful management of immunotherapy-related toxicity. 1

Key symptoms requiring clinical suspicion:

• Watery diarrhea with blood/mucus or severe abdominal cramping suggests colitis 1
• Dry cough coupled with shortness of breath may indicate pneumonitis 1
• New-onset peripheral neuropathy occurred in 12% of patients in clinical trials, with median onset 50 days 8

Treatment Interruption and Discontinuation

• Grade 1-2 events: withhold immunotherapy and initiate corticosteroids 4
• Grade 3-4 events: permanently discontinue immunotherapy and administer high-dose corticosteroids 4
• Corticosteroid tapering must occur gradually over at least 1 month to prevent relapse, planned with organ specialist 4

Efficacy Considerations

Anti-PD-1 monotherapy is preferred over combination therapy in patients with autoimmune disease due to lower toxicity risk while maintaining comparable efficacy. 5

• Severe irAEs leading to discontinuation occurred in up to 13% of patients receiving anti-PD-1 monotherapy versus higher rates with combination regimens 1
• In patients with pre-existing autoimmune disease, response rates with immunotherapy remain similar to the general population despite increased toxicity risk 5, 6