What is Immunotherapy?

Malignant tumors are the result of the abnormal transformation of normal cells, characterized by uncontrolled proliferation and the potential for metastasis. To survive and grow, tumor cells adopt various strategies to suppress the human immune system, preventing it from effectively killing tumor cells and enabling the cancer to evade immune responses at all stages of antitumor immunity.

In the immune system, cytotoxic T cells and NK cells play a central role in monitoring and eliminating tumor cells. When tumor cells proliferate uncontrollably and immune cell activity is weakened, they cannot effectively eliminate the cancer cells, leading to the development of severe diseases.

With advances in biotechnology, scientists can now design targeted therapies at the molecular and cellular levels for specific oncogenic sites, causing tumor cells to die selectively. While targeted therapies can precisely attack cancer cells, tumors often engage in a "cat-and-mouse" game with the immune system. These "cunning" cancer cells have adaptive abilities that enable them to evade immune surveillance and attack.

Common Immune Checkpoints

1. PD-1
   PD-1 is a transmembrane protein primarily expressed on activated CD4+ T cells, CD8+ T cells, B cells, NK cells, monocytes, and dendritic cells. Its main function is to promote T cell maturation. Normally, PD-1 regulates the differentiation of T cells in peripheral tissues to modulate immune responses to foreign or self-antigens, preventing excessive immune reactions.

2. B7-H1 (PD-L1)
   PD-L1 is a protein that negatively affects the immune system. It is mainly expressed on antigen-presenting cells, B cells, T cells, epithelial cells, muscle cells, endothelial cells, and tumor cells, and it plays a role in tumor-associated immune responses.
   PD-L1 is minimally expressed in normal tissues but is highly expressed in cancers such as lung cancer, colorectal cancer, and ovarian cancer. Since PD-L1 is primarily expressed on tumor cells, using PD-L1 antibodies to target and kill cancer cells is a promising immunotherapy strategy.

3. CTLA-4
   CTLA-4 is a transmembrane receptor on T cells. Binding between CTLA-4 and B7 molecules induces T cell anergy, negatively regulating immune responses. In 1996, James P. Allison’s team demonstrated that using CTLA-4 antibodies could enhance immune function and inhibit tumor growth.

Next, let’s discuss immune checkpoint inhibitors that block the immune-suppressive effects of these checkpoints, thereby reactivating and rebooting the immune system.

Common Immune Checkpoint Inhibitors

1. Nivolumab
   A fully human monoclonal antibody that blocks the interaction between PD-1 and its ligands PD-L1 or PD-L2. This reverses immune evasion by tumors, restores T cell antitumor activity, and inhibits tumor growth. Nivolumab was one of the first anti-PD-1 antibodies to enter clinical trials and is widely used in the treatment of various malignancies, showing promising results.

2. Pembrolizumab
   Approved by the FDA for treating advanced melanoma, this humanized monoclonal antibody inhibits PD-1 with high affinity, significantly reducing immunogenicity and adverse effects.

3. CTLA-4 Inhibitor Ipilimumab
   Ipilimumab is a fully human monoclonal antibody against CTLA-4. Initially approved in 2011 for the treatment of advanced melanoma, it is often used in combination therapies due to limited efficacy when used alone.

Predictive Factors for Tumor Immunotherapy

Immune checkpoint inhibitors do not produce uniform therapeutic effects in all patients. Some respond well to treatment, while others do not. What factors predict better responses to immunotherapy?

1. PD-L1 Expression
   Studies show that pembrolizumab is more effective in patients with high PD-L1 expression in advanced non-small cell lung cancer (NSCLC). The KEYNOTE-010 study demonstrated that PD-L1 can serve as a biomarker for predicting pembrolizumab efficacy.
   For NSCLC patients with ≥50% PD-L1 expression, pembrolizumab showed longer progression-free survival (PFS) and overall survival (OS) compared to platinum-based chemotherapy, with fewer adverse reactions. However, while high PD-L1 expression correlates with better outcomes, PD-L1 testing alone cannot always identify the most responsive groups.

2. Tumor Mutation Burden (TMB)
   TMB is defined as the number of mutations in the somatic genome. TMB determines tumor immunogenicity, while the tumor microenvironment affects T cell infiltration, distribution, and function. Genomic instability and deficient DNA repair can lead to hypermutation or microsatellite instability (MSI), increasing TMB.
   High TMB correlates with better outcomes from pembrolizumab and other checkpoint inhibitors.

3. Microsatellite Instability (MSI)
   MSI results from mismatch repair deficiency (dMMR), leading to high mutation levels and neoantigen production. Tumors with MSI are more sensitive to PD-1/PD-L1 inhibitors.

4. Interferon-γ (IFN-γ)
   IFN-γ, a protein with antiviral and antitumor properties, may serve as a potential biomarker for immune therapy efficacy, as higher IFN-γ signaling in biopsied tumors is associated with better responses to PD-1 inhibitors.

5. Tumor-Infiltrating Lymphocytes (TILs)
   Tumor immune microenvironments influence treatment efficacy. Specific TIL subsets, such as CTLA-4+PD-1+ T cells, correlate with the effectiveness of PD-1 antibodies.

6. Serum Markers
   In melanoma patients, high baseline eosinophil and lymphocyte counts combined with low lactate dehydrogenase levels were linked to better overall survival (OS) after pembrolizumab treatment.

7. Genomic Profiling
   Tumor genomic and transcriptomic analyses reveal resistance mechanisms and may guide precision immunotherapy.

Common Adverse Reactions

Immune-related adverse events (irAEs) associated with checkpoint inhibitors arise from disrupted immune homeostasis, potentially involving T cells, autoantibodies, and inflammatory cytokines. Most irAEs are mild and manageable.

1. Skin Reactions
   Skin reactions are the most common and earliest side effects, including itching, rash, dermatitis, erythema, urticaria, and vitiligo. Patients should use gentle skincare products, avoid UV exposure, and wear loose clothing to reduce risk.

2. Gastrointestinal Reactions
   Gastrointestinal side effects include diarrhea, abdominal pain, and nausea. Treatment depends on severity:

   • Mild symptoms: Antidiarrheal drugs, hydration, and electrolyte balance.
   • Moderate-to-severe symptoms: Immunosuppressants, corticosteroids, and discontinuation of therapy may be required.

3. Liver Injury
   Liver damage is less common but can occur, especially with combination therapies.

4. Immune-Related Pneumonitis
   Symptoms include dry cough, dyspnea, tachycardia, and fatigue. Treatment involves corticosteroids and discontinuation of therapy.

5. Autoimmune Endocrine Disorders
   These include thyroid dysfunction, hypophysitis, and adrenal insufficiency, typically manageable with corticosteroids.

Checkpoint inhibitors have ushered in a new era of cancer treatment, and identifying predictive biomarkers is key to precision immunotherapy. A combination of predictive factors will better identify patients likely to benefit, maximizing clinical outcomes.