Immune System as a Treatment Target

The immune system has become a target for cancer treatments in recent years.¹ The body’s immune system can detect and destroy abnormal cells and most likely prevent or slow the growth of many cancers.¹ However, cancer cells can avoid destruction by the immune system.¹ Immunotherapy has emerged as a type of cancer treatment that helps the immune system fight cancer.¹ There are several types of immunotherapy, including immune checkpoint inhibitors, chimeric antigen receptor (CAR) T-cell therapy, monoclonal antibodies, vaccines and immune system modulators.²

Immune Checkpoint Inhibition

Immune checkpoint inhibitors block checkpoint proteins, which allows immune cells to exhibit a stronger response to cancer.^1-4 Immune checkpoint inhibitors are approved by the U.S. Food and Drug Administration (FDA) for intravenous infusion to treat patients with various cancers, including breast cancer, cervical cancer, colon cancer, head and neck cancer, Hodgkin lymphoma, liver cancer, lung cancer, skin cancer, and other solid tumors.³ Drugs that target different checkpoint proteins are currently used to treat different types of cancer.⁴

CTLA-4

CTLA-4 is a checkpoint protein on T cells that prevents the “off” signal from being sent and allows the T cells to kill cancer cells.^1,4 CTLA-4 inhibitors include ipilimumab (Yervoy), the first immune checkpoint inhibitor approved by the FDA, and tremelimumab (Imjudo).⁴ These drugs are used to treat advanced melanoma and other cancers, in combination with a PD-1 or PD-L1 inhibitor.^4,5

PD-1 and PD-L1

PD-1 is another checkpoint protein on T cells.^4,5 When PD-1 attaches to PD-L1, a protein on normal and cancer cells, it instructs the T cell to leave the other cells alone.^4,5 Therapies that target PD-1 or PD-L1 can block this binding and boost immune response.⁴ PD-1 inhibitors include pembrolizumab (Keytruda), nivolumab (Opdivo) and cemiplimab (Libtayo), which are used to treat cancers of the bladder, breast, head and neck, Hodgkin lymphoma, melanoma and non-melanoma skin cancers, and non-small cell lung cancer.^4,5 Atezolizumab (Tecentriq), avelumab (Bavencio) and durvalumab (Imfinzi) are PD-L1 inhibitors used to treat cancers including bladder cancer, breast cancer, Merkel cell carcinoma and non-small cell lung cancer.^4,5

Emerging Tumor Targets

Research continues to focus on other checkpoint proteins and developing drugs that can be used to target them.^5-8A selection of new immune checkpoint targets includes:

LAG-3—works synergistically with PD-1 to induce immune suppression.^9-11 Targeted combination therapy may help overcome immune evasion.^9-11 A LAG-3 inhibitor is approved for advanced melanoma.¹⁰ This target is also being evaluated for lung, colorectal, liver, and esophageal or gastric cancers, multiple myeloma and chordoma.¹¹
MUC16—has been shown to modulate the innate immune response against ovarian cancer cells.¹² Although MUC16 has a protective role in normal physiology, it is also overexpressed in various cancers, with an important role in tumorigenicity, disease progression and acquired resistance to therapy.¹²
TLR-9—a known inducer of interferon production.¹³ TLR-9 is being looked at for melanoma, non-small cell lung cancer, breast cancer, and sarcoma.¹³
CD20/CD3—simultaneous binding of CD20, a B-cell surface antigen, and CD3, a T-cell activator, has demonstrated promising clinical activity against B-cell lymphoma.¹⁴
BCMA—a specific and highly expressed antigen on myeloma cells is being looked at as a promising target for therapies for multiple myeloma.¹⁵
VISTA—an immunoregulatory molecule involving in maintaining T-cell and myeloid quiescence, is being investigated as a target for therapies for melanoma, renal cell carcinoma, prostate, non-small cell lung, acute myeloid leukemia, colorectal, ovarian and endometrial cancers.¹⁶

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