Immunomodulators
CHECKPOINT INHIBITORS, CYTOKINES, AGONISTS, AND ADJUVANTS

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Immunomodulators: Checkpoint Inhibitors, Cytokines, Agonists, and Adjuvants

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

As we’ve learned more about these brakes and gas pedals of the immune system, we 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 2019, 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.

Checkpoint Inhibitor

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

Adoptive Cell Therapy

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 for melanoma. As of the end of 2018, the FDA has approved seven checkpoint inhibitors for eleven 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 promoting the activation of “killer” T cells, which directly attack cancer cells, as well as 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 innate immune pathways 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 twelve different immunomodulators—seven checkpoint inhibitors, four cytokines, and one adjuvant—for the treatment of eleven 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 first-line options in several cancer types.

Checkpoint Inhibitors

  • Atezolizumab (Tecentriq®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with bladder cancer and lung cancer
  • Avelumab (Bavencio®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with bladder 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, a type of skin cancer
  • Durvalumab (ImfinziTM): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with bladder cancer and lung cancer
  • Ipilimumab (Yervoy®): a checkpoint inhibitor that targets the CTLA-4 pathway; approved for subsets of patients with melanoma
  • Nivolumab (Opdivo®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with bladder cancer, colorectal cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, lymphoma, and melanoma
  • Pembrolizumab (Keytruda®):a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with bladder cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, lymphoma, melanoma, and stomach cancer

Cytokines

  • Aldesleukin (Proleukin®): a cytokine that targets the IL-2/IL-2R pathway; approved for subsets of patients with kidney cancer and melanoma
  • 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

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

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

Side Effects

Side effects can vary according to the type of immunomodulator—and what exactly it targets—and can 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 can lead the immune system to overactive immune responses as well off-target responses against healthy cells, both of which can lead to side effects.

These side effects can range from mild to moderate and can become deadly under certain circumstances. Fortunately, in most cases side effects can be safely managed as long as they are recognized and addressed early. Therefore, it’s extremely important that patients notify their care team as soon as possible about any unusual developments during or after treatment with 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.

The side effects most commonly associated with currently approved checkpoint immunotherapies are: asthenia, colitis, arthralgias, constipation, cough, decreased appetite, diarrhea, dyspnea, fatigue, headache, infusion-related reactions, insomnia, nausea, pain (including in the abdomen, back, and musculoskeletal system), peripheral edema, pneumonitis/radiation pneumonitis, pruritus, pyrexia, rash, vomiting, and weight loss.

The side effects most commonly associated with currently approved cytokine immunotherapies are: bilirubinemia, chills, confusion, diarrhea, dyspnea, fatigue, fever, flu-like symptoms, headache, hypotension, myalgia, nausea, oliguria, rash, thrombocytopenia, vomiting. For more information regarding the side effects associated with immunomodulators and other immunotherapy approaches, please refer to our immunotherapy side effects webpage. 

CRI’s Impact in Immunomodulators

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

  • In 1995, CRI postdoctoral fellow Frank Borriello, M.D., Ph.D., and Arlene Sharpe, M.D., Ph.D., 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, Ph.D., and CRI Grantee Ralph Steinman discovered that the CD40 pathway is required for adaptive immunity. This paved the way for a CRI-funded trial led by Robert Vonderheide, M.D., D.Phil., a member of CRI’s Scientific Advisory Council, that targets the CD40 pathway in combination with chemotherapy and checkpoint immunotherapy in patients with metastatic pancreatic cancer, which was launched in 2017.
  • • In 2006, CRI postdoctoral fellows E. John Wherry, Ph.D., and David Masopust, Ph.D., along with Rafi Ahmed, Ph.D., revealed that targeting the PD-1 immune checkpoint can restores the activity of “exhausted” T cells, paving the way for the application of this strategy in cancer patients.
  • In 2010, Drew Pardoll, M.D., Ph.D., who received his first grant ever from CRI in 1988 (and has been supported by CRI essentially ever since), 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 and fellow CRI-SU2C Dream Team member Suzanne Topalian, M.D., Ph.D., highlighted the potential benefits of anti-PD-1 checkpoint immunotherapy prior to surgery in patients with lung cancer.
  • In 2014, Antoni Ribas, M.D., Ph.D., a member of the CRI-SU2C Dream Team, identified patient traits that could predict responses to checkpoint immunotherapy. In 2016, Ribas, along with fellow Dream Team member Ton Schumacher, Ph.D., and CRI-funded CLIP investigator, Roger Lo, M.D., Ph.D., identified mutations that were associated with resistance to checkpoint immunotherapy.

In addition to eleven active, CRI-funded clinical trials using immunomodulators, CRI currently funds grantees who are conducting research focusing on cancer vaccines.

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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 their cancer-eating activity
  • 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

In addition to these immunomodulatory targets currently being evaluated in clinical trials, new targets and immunotherapy approaches are constantly being developed and investigated in clinical trials. To determine if you or someone you know might be eligible for an immunotherapy clinical trial, please consult our Clinical Trial Finder service.

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Sources: CRI documents; U.S. Food and Drug Administration (FDA); FDA Hematology/Oncology (Cancer) Approvals & Safety Notifications; FDA Online Label Repository

Updated August 2019

*Immunotherapy results may vary from patient to patient. Consult a health care professional about your treatment options.

*Immunotherapy results may vary from patient to patient.

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