Introduction
Immunotherapy has reformed cancer treatment by utilizing the immune system to fight cancer cells. Combining immunotherapies can activate the immune response, yielding more durable results compared to single treatments. Ongoing clinical investigations show promising outcomes.
What Are the Immunotherapy Combinations Used in Oncology?
Immunotherapy combination is a treatment approach that involves using multiple immunotherapeutic agents, such as checkpoint inhibitors, cancer vaccines, chimeric antigen receptor (CAR) T-cell therapy, and cytokine therapy, alongside other treatments like chemotherapy, radiotherapy, or targeted therapy. This strategy aims to achieve durable anti-cancer effects and improve treatment outcomes. The types of immunotherapy combinations are:
1. Immune Checkpoint Inhibitors: These are a type of drug that inhibit proteins called checkpoint molecules. Some include:
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Programmed Cell Death-1 (PD-1) Blockade and Combinations: PD-1 is a receptor found on immune cells. It interacts with ligands called PD-L1 and PD-L2, which are present on immune cells and tumor cells. When PD-1 binds to its ligands, it suppresses the immune response, leading to the inability of immune cells to attack cancer cells effectively. To improve its effectiveness, researchers are testing combinations of PD-1/PD-L1 inhibitors with other therapies like chemotherapy, targeted therapies, and radiation. These combination approaches have demonstrated better responses in some studies, such as Hodgkin's lymphoma, pancreatic cancer, and breast cancer.
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Cytotoxic T-Lymphocyte-Associated Protein-4 (CTLA-4) Blockade and Combinations: Similar to PD-1, CTLA-4 is another immune system checkpoint that negatively regulates T cells. It limits T cell responses early in the immune response, whereas PD-1 acts later. Blockade of CTLA-4 activates T cells and may reduce regulatory T cells in the tumor microenvironment. One of the largest trials of CTLA-4 blockade tested Ipilimumab in advanced melanoma patients, showing improved survival compared to a vaccine or Ipilimumab alone.
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Combination of Anti-PD-1/PD-L1 and Anti-CTLA-4: In recent years, monotherapy with drugs like Nivolumab and Ipilimumab has shown promise in cancer treatment, providing durable responses and high response rates in certain patients. In a study on metastatic colorectal cancer patients with specific genetic features, Nivolumab in combination with Ipilimumab showed higher response rates compared to Nivolumab alone. However, this combination may also lead to higher treatment-related adverse events.
2. Checkpoint Molecules: These are specific proteins that play important roles in regulating the immune response. Some of the molecules being explored are:
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T Cell Immunoglobulin and Mucin Domain 3 (Tim-3): It is a protein found on immune cells and acts as a regulator in the immune system. It can either promote immune responses or inhibit them, making it a dual-function protein. Tim-3 is considered a negative checkpoint molecule because it can lead to immune exhaustion. Blocking Tim-3 with antibodies has shown promising results in enhancing anti-tumor effects, especially when combined with other checkpoint inhibitors.
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V-Domain Ig Suppressor of T Cell Activation (VISTA): Also known as programmed death protein 1 homolog (PD-1H), VISTA serves as a negative regulator of T cell responses. By suppressing the immune system, VISTA helps prevent excessive immune reactions that could potentially cause tissue damage and autoimmunity.
3. Co-stimulatory Molecules: These are proteins that play a vital role in regulating the immune system by providing additional signals. Some examples include:
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4-1BB: Also known as TNFRSF9 (tumor necrosis factor receptor superfamily member 9), it is found in immune cells such as dendritic cells, T cells, and Natural Killer (NK) cells. When 4-1BB connects with its partner molecule 4-1BB-L, which is present in other immune cells, it helps in killing cancer cells.
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OX40: Also known as CD134 and TNFRSF4 (tumor necrosis factor receptor superfamily member 4), it is a type of receptor molecule found on immune cells like T cells. It activates and multiplies immune cells by interacting with its ligand called OX40L.
4. Cellular Immunotherapy: It is a type of cancer treatment that uses the body's own immune cells or modified immune cells to recognize and destroy cancer cells. Some types of cellular immunotherapy include:
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Tumor-Infiltrating Lymphocyte (TIL) Therapy and Combinations: This treatment involves collecting immune cells, such as T cells, and modifying them to make them better at killing cancer cells. Once these modified cells multiply enough, they are infused back into the patient's body. TIL therapy is used for metastatic melanoma, a type of skin cancer. It has shown promising results, especially in patients who have not received checkpoint inhibitors before and also in patients who have been treated with anti-CTLA-4 or anti-PD-1 drugs. This therapy has been associated with a lower rate of cancer recurrence. When combined with vemurafenib in patients with a specific gene mutation (BRAF V600E/K), TIL therapy has shown encouraging outcomes.
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Chimeric Antigen Receptor (CAR) T Cell Therapy and Combinations: CAR T cell therapy is a type of immunotherapy that uses modified T cells with chimeric antigen receptors on their surface. These receptors enable the T cells to recognize specific antigens present in cancer cells. Once the T cells are modified, they are infused back into the patient's body to seek out and destroy cancer cells. CAR T cell therapy has shown remarkable success in treating certain blood cancers like leukemia and lymphoma. There are various combination approaches being explored to enhance the effectiveness of CAR T cell therapy. These combinations include using checkpoint inhibitors, cancer vaccines, radiation therapy, chemotherapy, and adoptive cell therapy. Adoptive cell therapy involves infusing tumor-infiltrating lymphocytes (TILs), which are immune cells that have already infiltrated the tumor. The goal of these combinations is to improve cancer treatment outcomes and provide better results for patients.
5. Combination of Radiation Therapy and Immunotherapy: This combination therapy enhances the body's ability to fight cancer cells. Radiation therapy is used when tumors cannot be removed surgically and can damage cancer DNA (deoxyribonucleic acid) while activating T cells. When used with immunotherapy, it further stimulates the immune system. The synergistic effects include improved immune response, increased tumor infiltration, and recognition of cancer cells in other parts of the body, called the abscopal effect. The abscopal effect is a phenomenon where cancer cells undergoing death release tumor antigens, signaling the immune system. Immune cells, like antigen-presenting cells (APCs), recognize these antigens and present them to T cells. These activated T cells then travel to distant sites and attack cancer cells, leading to a systemic anti-tumor response. Additionally, this combination can overcome resistance seen in some tumors.
6. Combination of Cancer Vaccines with Chemotherapy: Cancer vaccines aim to activate the immune system to recognize and fight cancer cells. The p53 gene, a tumor suppressor gene, is frequently mutated in cancer. A tumor protein p53 cancer vaccine can help stimulate T cell responses against p53 peptides. When combined with chemotherapy like Cisplatin/VP-16 (Cisplatin and Etoposide) or Carboplatin/VP-16 (Carboplatin and Etoposide), it has been shown to improve prognosis by developing an antigen-specific response. Similarly, other cancer vaccines combined with chemotherapy agents such as Irinotecan, Docetaxel, and Gemcitabine have demonstrated improved survival rates.
7. Biomarkers in Immunotherapy Combinations: Biomarkers are indicators that help predict patients' responses to treatments. Some biomarkers used in immunotherapy combinations include PD-L1 expression, which predicts the effectiveness of immune checkpoint inhibitors. Another biomarker is tumor mutational burden (TMB), measuring the number of mutations in the tumor's DNA. Higher TMB is associated with better treatment response.
What Are the Advantages of Combining Different Immunotherapy Agents in Cancer Treatment?
The advantages include:
- Combining these agents can activate multiple pathways, resulting in a more robust and coordinated immune response against the cancer.
- Combining therapies with different mechanisms of action can make it more challenging for cancer cells to develop resistance.
- Some immunotherapy agents have complementary effects. When used together, they can create a synergistic effect, where the combined therapy is more potent than the individual agents alone.
- Different patients may respond differently to immunotherapy agents. Combining agents can allow for more personalized treatment approaches.
- Combining immunotherapy agents may allow for lower individual doses of each agent, potentially reducing the risk of adverse side effects while maintaining therapeutic efficacy.
Conclusion:
Immunotherapy, when combined with other treatments like surgery, chemotherapy, and radiotherapy, has shown successful outcomes in various clinical studies. Ongoing developments and FDA (food and drug administration) approvals make them powerful tools in cancer treatment. However, they can also lead to side effects such as drug-induced toxicity and lower efficacy rates.
