Clinical Response and Mechanisms of Resistance to Checkpoint Blockade Therapy

Clinical Response to Checkpoint Blockade Therapy

Immune Checkpoint blockade (ICB) therapy, particularly immune checkpoint inhibitors targeting molecules like PD-1, PD-L1, and CTLA-4, has shown significant clinical responses in various cancer types, including melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer, head and neck squamous cell carcinoma, MSI-high colorectal carcinoma, Merkel cell carcinoma, and Hodgkin lymphoma, and have changed the practice of medical oncology. The clinical response to checkpoint blockade therapy can manifest in several ways, including objective response rate (RR), prolonged disease stabilization, durable responses, overall survival, etc.

Immune checkpoint inhibitor (ICI) therapy has been especially effective in melanoma, where approved treatments now include anti-PD-1, anti-CTLA-4, and anti-PD-1/CTLA-4 combinations. Long-range survival data for melanoma patients treated with anti-CTLA-4 show that 20% of patients continue to have sustained disease control or response 5-10 years after initiating therapy. At three years, the response rate for melanoma patients treated with anti-PD-1 was 33%, with 70-80% of patients who initially responded retaining clinical response. In patients with metastatic melanoma, combination immunotherapy or dual immune checkpoint inhibition (anti-PD-1⁺anti-CTLA-4) has recently shown significant response rates (RR 58%).

Mechanisms of Resistance to Checkpoint Blockade Therapy

While checkpoint blockade therapy has shown significant success, drug resistance to medicines targeting immune checkpoints is a key limitation for immunotherapy patients. Many studies are being performed to elucidate the functional processes driving ICB resistance. Several mechanisms of resistance have been identified:

• Innate (Primary) and Acquired (Secondary) Resistance
  The majority of cancer cell intrinsic elements lead to primary resistance. Primary resistance is caused by a lack of tumor immunogenicity, inadequate CD8⁺ T-cell infiltration, and irreversible T-cell exhaustion. For example, tumors can evolve to escape both the innate and adaptive immune systems, rendering ICI therapy ineffective. Partially exhausted PD-1⁺ CTLA-4⁺ CD8⁺ infiltrating T cells have been linked to PD-1 responsiveness. Furthermore, anti-CTLA-4 antibody therapy is used to generate ICI-resistant cells, which enhances Treg depletion. Some patients who initially respond develop resistance or relapse, which is recognized as acquired resistance. Impaired formation of T-cell memory can cause acquired resistance.
• Tumor-Derived Resistance
  Tumor cell genetic and epigenetic changes are the intrinsic and tractive mechanism that drives ICB resistance. When tumor cells are stressed by ICBs, they inhibit immune cells from recognizing and killing them, and they promote immune evasion, excessive growth, recurrence, and metastasis.
• T Cell-Based Resistance
  T lymphocytes play critical roles in the immune response to malignancy. The killing effect of T cells is usually derepressed by ICBs to restore its identification and cytolytic effect on cancer cells during the action of ICBs. The therapeutic impact of ICB decreases when the functional phenotype of these reactivated anti-tumor T cells changes. In terms of T cell modification, ICB resistance is primarily governed by T cell quantity, distribution, effect, and activation state.
• Tumor Microenvironment-Determined Resistance
  Apart from tumor cells and T-cells, the diverse range of other functional components within the TME suggests a distinct pool of key modulators of immune actions against cancer. Immunosuppressive cells, chemicals, cytokines, and chemokines are the most common modulators.

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