Immunotherapy:
Immunomodulators

Immunomodulators: Checkpoint Inhibitors, Cytokines, Agonists, and Adjuvants

Reviewed by:

Jason Luke, MD, FACP
University of Pittsburgh Medical Center

Immunomodulators are molecules that act on the pathways that regulate the immune system’s activity.

As scientists have learned more about the brakes and gas pedals of the immune system, they have been able to develop therapies that can target both in order to improve the immune system’s ability to attack and eliminate cancer. With respect to the different types of immunomodulators, they can be roughly divided into four categories: checkpoint inhibitors, cytokines, agonists, and adjuvants.

Checkpoint Inhibitors

Checkpoint inhibitors work by blocking immune checkpoints—the “brakes” of the immune system—that tumors frequently manipulate in order to shut down immune responses and protect themselves. As a result, checkpoint inhibitors are able to unleash new immune responses against cancer as well as enhance existing responses to promote elimination of cancer cells. As of 2020, checkpoint inhibitors are perhaps the most well-known, and most widely successful, immunomodulators developed so far.

For example, PD-1/PD-L1 immune checkpoint pathway can shut down cancer-targeting T cells.

However, when checkpoint inhibitors block the PD-1/PD-L1 pathway, they can enable T cells to eliminate cancer cells.

In 2011, the U.S. Food and Drug Administration (FDA) approved the first checkpoint inhibitor immunotherapy for the treatment of cancer—the CTLA-4-blocking ipilimumab (Yervoy®) for melanoma. Since then, the FDA has approved seven checkpoint inhibitors to treat more than a dozen different types of cancer. Due to their potential to enhance the effectiveness of immune responses, many different checkpoint inhibitors are currently being evaluated, both alone and in combination with other treatments, in a variety of cancer types in clinical trials.

Cytokines

Cytokines are messenger molecules that regulate immune cell maturation, growth, and responsiveness. Currently, there are four FDA-approved cytokine immunotherapies—for the treatment of subsets of patients with kidney cancer, leukemia, lymphoma, melanoma, and sarcoma.

Agonists

Agonists activate pathways that promote adaptive immune responses, either by helping to activate “killer” T cells, which directly attack cancer cells, or stimulating the activity of innate immune cells like dendritic cells, which coordinate overall immune responses against cancer by displaying cancer markers and enhancing T cell activity.

Adjuvants

Adjuvants activate pathways involved in the innate immune system that can stimulate general immune responses and ultimately promote adaptive immune responses. One FDA-approved adjuvant immunotherapy is currently available for the treatment of subsets of patients with squamous cell carcinoma, a type of skin cancer.

Treatment Options

Currently, the FDA has approved 16 different immunomodulators—nine checkpoint inhibitors, four cytokines, two adjuvants, and a small molecule with immunomodulatory properties—for the treatment of more than a dozen major cancer types. Most of these approvals cover cancers that are advanced or resistant to other forms of treatment, but more recently they’ve also been approved as the first systemic treatment a patient receives for several types of metastatic cancer.

Checkpoint Inhibitors

• Atezolizumab (Tecentriq®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with bladder cancer, breast cancer, liver cancer, lung cancer, melanoma, and sarcoma
• Avelumab (Bavencio®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with bladder cancer, kidney cancer, and Merkel cell carcinoma, a type of skin cancer
• Cemiplimab (Libtayo®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with cutaneous squamous cell carcinoma, basal cell carcinoma, and lung cancer
• Dostarlimab (Jemperli): a checkpoint inhibitor that targets the PD-1 pathway; approved for subsets of patients with uterine (endometrial) cancer
• Durvalumab (Imfinzi™): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with bladder cancer, liver cancer, and lung cancer
• Ipilimumab (Yervoy®): a checkpoint inhibitor that targets the CTLA-4 pathway; approved for subsets of patients with melanoma, mesothelioma, liver cancer, and lung cancer
• Nivolumab (Opdivo®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, lymphoma, melanoma, and mesothelioma
• Pembrolizumab (Keytruda®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with bladder cancer, breast cancer, cervical cancer, colorectal cancer, cutaneous squamous cell carcinoma, esophageal cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell carcinoma, and stomach cancer. It is also approved to treat subsets of patients with cancers of any type that present with certain genetic mutations (MSI-H, dMMR, or TMB-H).
• Relatlimab: a checkpoint inhibitor that targets the LAG-3 pathway; approved in combination with nivolumab (together known as Opdualag™) for subsets of patients with melanoma
• Retifanlimab (Zynyz): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced Merkel cell carcinoma
• Tremelimumab (Imjudo®): a checkpoint inhibitor that targets the CTLA-4 pathway; approved in combination with durvalumab and chemotherapy for subsets of patients with liver cancer and lung cancer

Cytokines

• Aldesleukin (Proleukin®): a cytokine that targets the IL-2/IL-2R pathway; approved for subsets of patients with kidney cancer and melanoma
• Granulocyte-macrophage colony-stimulating factor (GM-CSF): an immunomodulatory cytokine; approved for subsets of patients with neuroblastoma
• Interferon alfa-2a: a cytokine that targets the IFNAR1/2 pathway; approved for subsets of patients with leukemia and sarcoma
• Interferon alfa-2b (Intron A®): a cytokine that targets the IFNAR1/2 pathway; approved for subsets of patients with leukemia, lymphoma, melanoma, and sarcoma
• Peginterferon alfa-2b (Sylatron®/PEG-Intron®): a cytokine that targets the IFNAR1 pathway; approved for subsets of patients with melanoma

Adjuvants

• Imiquimod: an immune adjuvant targeting the Toll-like receptor 7 (TLR7) pathway; approved for subsets of patients with basal cell carcinoma
• Poly ICLC (Hiltonol®): an immune adjuvant targeting the Toll-like receptor 3 (TLR3) pathway; approved for subsets of patients with squamous cell carcinoma

Other Immunomodulators

• Pexidartinib (Turalio™): a small molecule inhibitor of the KIT, CSF1R, and FLT3 pathways; approved for a subset of patients with tenosynovial giant cell tumor

Due to their effect on overall immune activity and their ability to stimulate immune responses, immunomodulators may cause side effects.

Side Effects

Potential side effects may vary according to the type of immunomodulator—and what exactly it targets—and may also be influenced by the location and type of cancer as well as a patient’s overall health. Sometimes the manipulation of the immune system’s brakes and gas pedals via immunomodulators may lead to overactive immune responses as well off-target responses against healthy cells, both of which may lead to side effects.

Immunomodulator-related side effects can range from mild to moderate and can become potentially life-threatening under certain circumstances. Fortunately, in most cases potential side effects can be safely managed as long as they are recognized and addressed early. Therefore, it’s extremely important that patients notify their medical care team as soon as possible if they experience any unusual symptoms during or after treatment with cancer immunotherapy. In addition, patients should always consult their doctors and the rest of their care team to gain a better and fuller understanding of the potential risks and side effects associated with specific immunomodulators.

Common side effects associated with currently approved checkpoint immunotherapies may include but are not limited to: fatigue, rash, colitis, infusion-related reactions, diarrhea, asthenia, arthralgias, constipation, decreased appetite cough, dyspnea, headache, insomnia, nausea, pain (including in the abdomen, back, and musculoskeletal system), peripheral edema, pneumonitis/radiation pneumonitis, pruritus, pyrexia, vomiting, and weight loss.

Common side effects associated with currently approved cytokine immunotherapies may include but are not limited to bilirubinemia, chills, confusion, diarrhea, dyspnea, fatigue, fever, flu-like symptoms, headache, hypotension, myalgia, nausea, oliguria, rash, thrombocytopenia, and vomiting.

CRI’s Impact in Immunomodulators

Throughout CRI’s history, we have supported a variety of basic research projects aimed at improving our understanding of the mechanisms of the immune system’s many brakes and gas pedals. We have also supported translational and clinical efforts that seek to use these insights in the development of immunomodulators for the treatment of cancer patients in the clinic.

One notable grantee is Drew Pardoll, MD, PhD, of the Johns Hopkins University School of Medicine, received his first grant from CRI in 1988 and has been supported by CRI ever since. In 2010, he revealed the benefits of anti-PD-1 immunotherapy in several types of advanced cancers, helping to establish immunotherapy’s promise in the clinic. In 2018, Dr. Pardoll along with his colleague and wife, Suzanne Topalian, MD, PhD, also of Johns Hopkins, highlighted the potential benefits of anti-PD-1 checkpoint immunotherapy prior to surgery in patients with lung cancer.

Other CRI-funded research into immunomodulators includes:

• In 1995, CRI postdoctoral fellow Frank Borriello, MD, PhD, and Arlene Sharpe, MD, PhD, both of Harvard Medical School, demonstrated that the CTLA-4 checkpoint pathway suppresses immune activity, paving the way for clinical immunotherapies targeting CTLA-4.
• In 2004, CRI predoctoral fellow Kang Liu, PhD, and CRI grantee and Nobel Prize winner Ralph Steinman, MD, both of The Rockefeller University, discovered that the CD40 pathway is required for adaptive immunity.
• Their CD40 work paved the way for a CRI-funded trial led by CRI Scientific Advisory Council member Robert Vonderheide, MD, DPhil, of the Abramson Cancer Center at the University of Pennsylvania, that targets the CD40 pathway in combination with chemotherapy and checkpoint immunotherapy in patients with metastatic pancreatic cancer. Interim results released in early 2019 showed promising responses in a majority of patients treated with the combination.
• In 2006, CRI postdoctoral fellows E. John Wherry, PhD, and David Masopust, PhD, along with Rafi Ahmed, PhD, all of Emory University, revealed that targeting the PD-1 immune checkpoint can restore the activity of “exhausted” T cells, laying groundwork for the application of this strategy in cancer patients.
• In 2014, the University of California, Los Angeles (UCLA)’s Antoni Ribas, MD, PhD, identified patient traits that could predict responses to checkpoint immunotherapy. In 2016, Ribas, along with colleagues Ton Schumacher, PhD, of the Netherlands Cancer Institute, and CRI-funded CLIP investigator, Roger Lo, MD, PhD, also of UCLA, identified mutations that were associated with resistance to checkpoint immunotherapy.

Currently, CRI is funding several grantees whose research involves immunomodulators, including investigating the epigenetics of T cell exhaustion in the context of checkpoint immunotherapy, exploring the potential role of checkpoint immunotherapy in fibrolamellar hepatocellular carcinoma, and evaluating the potential value of various biomarkers relating to the success of checkpoint immunotherapy in patients with glioblastoma. Additionally, CRI is currently providing funding support for the several clinical trials involving immunomodulators, including for prostate cancer, pancreatic cancer, and lung cancer.

Immunomodulator Clinical Trial Targets

Immunomodulator targets under evaluation in clinical trials include:

• CD40: Activating this co-stimulatory pathway can kickstart adaptive immune responses
• CD47: This surface protein acts as a “don’t eat me!” signal that protects cancer from being consumed by certain immune cells; blocking CD47 can improve anti-tumor function of these immune cells
• CD73 or A2AR: Blocking these pathways can help prevent the production of immunosuppressive adenosine
• CD137 (also known as 4-1BB): activating this co-stimulatory pathway can help promote the growth, survival, and activity of cancer-fighting T cells
• CSF1/CSF1R: blocking this pathway can help reprogram cancer-supporting macrophages
• CTLA-4: blocking this pathway can help promote expansion and diversification of cancer-fighting T cells
• CXCR4: blocking this pathway can promote the migration and recruitment of immune cells
• GITR: activating this pathway can help prevent immunosuppression and increase the survival of cancer-fighting T cells
• ICOS: activating this co-stimulatory pathway on T cells can help enhance immune responses against cancer

• IDO: blocking this enzyme’s activity can help prevent cancer-fighting T cells from being suppressed
• IL-2/IL-2R: activating this cytokine pathway can help promote the growth and expansion of cancer-fighting T cells
• LAG3: blocking this pathway may be able to help prevent suppression of cancer-fighting T cells
• OX40: activating this co-stimulatory pathway can help promote T cell survival after activation
• PD-1/PD-L1: blocking this pathway can help prevent cancer-fighting T cells from becoming “exhausted,” and can restore the activity of already-exhausted T cells
• STAT3: activating this intracellular signaling protein can help stimulate adaptive immune responses
• STING: activating this protein in the DNA-sensing pathway can help stimulate immune responses against threats such as viruses and cancer
• Toll-like receptors (TLRs): activation of these innate immune receptors can help stimulate vaccine-like responses against tumors
• TIGIT: blocking this pathway may be able to help prevent suppression of cancer-fighting T cells
• TIM3: blocking this pathway may be able to help prevent suppression of cancer-fighting T cells

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