Across All Cancer Types
The Tumor Mutational Burden: Scientists at Johns Hopkins are trying to understand why some types of cancers respond better to immune checkpoint inhibitors. One important factor is the number of mutations present in a tumor's DNA (this is called the tumor mutational burden, or TMB). Cancers with a higher TMB might may appear more “foreign” to the body’s immune system, and are more easily recognized and eliminated by the immune system. Therefore, a higher number of mutations generally predicts a higher success rate with cancer immunotherapies.
See how the TMB impacts the response to cancer immunotherapy.
- Use the online tool.
- Watch Elizabeth Jaffee and Mark Yarchoan discuss a free tool doctors can use to calculate the tumor mutational burden in a patient and assess their receptiveness to immunotherapy treatment.
Read more about how more tumor mutations equals higher success rate with cancer immunotherapy drugs.
Mismatch Is Ideal Match for Immunotherapy: Bloomberg~Kimmel Institute\Ludwig Center investigators linked a DNA spell-check type of error, known as mismatch repair deficiency, to response to immunotherapy, leading to FDA approval of the drug pembrolizumab for patients whose cancers contain this genetic repair defect. It is the first time a drug has been approved based on a specific genetic profile without regard to where in the body the cancer started. Dung Le, M.D., led the clinical trial that prompted the FDA approval.
New Immunotherapy Drug: In an early clinical trial, a new drug called CPI-444 appears to keep cancer in check, alone and in combination with another immunotherapy. The drug targets the adenosine pathway, which acts as an on/off switch for cancer-attacking immune T cells. The trial has 11 participating hospitals, and cancer immunology expert Leisha Emens, M.D., Ph.D., is leading the study at the Bloomberg~Kimmel Institute. The drug is being tested in triple-negative breast cancer, lung cancer, kidney cancer, melanoma and other cancers.
New Type of Immunotherapy: In a Bloomberg~Kimmel Institute/Ludwig Center collaboration, researchers invented a new type of cancer drug called MANAbodies. Although still experimental, this first-of-its-kind immunotherapy targets the proteins from the abnormal gene mutations that drive cancer growth. This new discovery, led by Drew Pardoll, M.D., Ph.D., the Martin D. Abeloff Professor of Oncology, and Bert Vogelstein, M.D., the Clayton Professor of Oncology, is a clever mix of cancer immunology and cancer genetics. In essence, the researchers are taking the cancer-specific genetic mistakes that hide inside cancer cells and transforming them into red flags on the outside of cancer cells that can be recognized by MANAbodies.
Cancer-Seeking T Cells: MILs, or marrow-infiltrating lymphocytes, are a new type of immunotherapy developed by Ivan Borrello, M.D., to invoke a type of immune T cell that recognizes cancer. MILs are collected from the patient's bone marrow and expanded to larger numbers before they are given back to the patient through an IV. MILs have been successfully used to treat multiple myeloma, and Borrello and team are also developing MILs to treat lung cancer, esophageal cancer, HPV+ head and neck cancer and prostate cancer.
Gene Expression Is a Likely Key to Immunotherapy Response: Investigators made major headway in solving the mystery of why immunotherapies work so well in some patients and not others. New research by Bloomberg~Kimmel Institute Associate Director Suzanne Topalian, M.D., and collaborators at Memorial Sloan Kettering Cancer Center points to gene activity as an important cause underlying these varied responses. They found that certain genes in progressing tumors ramped up their activity, some by 2,000-fold. This activity can dampen the immune cell response ignited by immunotherapy. They are studying new and existing drugs’ ability to tamp down the activity of these barrier and immune-suppressive proteins.
Discarding the Evidence: An in-depth genetic analysis on tumor samples from patients before treatment with immunotherapy and again when the treatment stopped working led researchers Victor Velculescu, M.D., Ph.D., Valsamo Anagnostou M.D., Ph.D., and Kellie Smith, Ph.D., to uncover a key way cancers become resistant to immunotherapy drugs known as checkpoint inhibitors. Their genetic analysis revealed that cancers get rid of genetic cues that flag the cell for destruction by the immune system. When the cancer cells shed these mutations, they discard the evidence that would normally lead them to be recognized by the body’s protective immune cells. They are investigating how broadly the process occurs in lung and other cancer types to develop new ways to improve current cancer immunotherapies.
By Cancer Type:
Lung Cancer Patients Beating the Odds: A summary of clinical trial data from 129 non-small cell lung cancer patients treated since 2010 shows that immunotherapy has led to a dramatic improvement in survival rates. Patients who received the drug nivolumab, an immunotherapy that makes cancer cells visible to the immune system, have a five-year or more survival rate of 16 percent, compared to average survival rates of 1 to 4 percent, generally seen before this treatment became available. Julie Brahmer, M.D., director of the Kimmel Cancer’s Center’s Thoracic Center of Excellence, led the first immunotherapy trials in lung cancer. Brahmer and colleagues are working to extend this response to more patients and have already uncovered specific genes shared by patients that have lasting responses to immunotherapy that they believe could be linked to long-term survival.
Immunotherapy Before Surgery for Lung Cancer: In a small clinical trial of immunotherapy given four weeks before surgery to patients with non-small cell lung cancer, the treatment worked so well that by the time of surgery, the tumors in many patients had nearly or completely disappeared. This study, led by Patrick Forde, M.B.B.Ch., shows that immunotherapy may be a better option. Just two treatments with a type of immunotherapy known as a checkpoint inhibitor prompted an aggressive immune attack against the cancer in nine of the 21 patients treated. Forde and his colleagues plan to study a combination of checkpoint inhibitors before surgery and a longer duration of preoperative therapy to see if they can get similar results in more patients.
Melanoma Program director Suzanne Topalian along with lab members January Salas, Tracee McMiller and Shuming Chen, work on therapies to help the immune system attack cancer.
Melanoma Immunotherapy Combo: Research suggests combining two immunotherapies may improve survival rates for melanoma patients. Checkpoint inhibitors are a promising new type of cancer immunotherapy that makes cancer cells visible to the immune system, helping to stimulate immune cells to attack the cancer, but they don’t work in all patients. Evan J. Lipson, M.D., combined two checkpoint inhibitors, targeting the immune-inhibiting proteins PD-1 and LAG-3, in patients with advanced melanoma. Ongoing clinical trials are testing this drug combination in patients with other types of cancer and examining the benefit of adding a third checkpoint inhibitor.
Hope for Advanced Melanoma: William Sharfman, M.D., the Mary Jo Rogers Professor in Cancer Immunology and Melanoma Research, continues to lead clinical trials of experimental immunotherapies in melanoma patients whose cancers have not responded to or progressed on standard therapies. He has initiated two clinical trials, one that involves combining two immunotherapies and paves the way for what Sharfman refers to as the “triple threat”—a combination of three drugs aimed at over-powering cancer by hitting it on multiple fronts. Sharfman is also studying immunotherapy in combination with targeted therapies, treatments that inhibit specific genetic alterations that are driving a cancer’s growth and spread.
Immunoswitch: A nanoparticle developed by Jonathan Schneck, M.D., Ph.D., and team acts like an “immunoswitch,” making cancer cells visible to the immune system and stimulating the immune system to attack cancer cells. The researchers placed two different kinds of antibodies on the nanoparticle. One antibody blocks a protein called PD-L1 and turns off cancer cells’ ability to hide from immune cells, and the other antibody turns up the activity of cancer-attacking immune T cells.
Combining these two functions switches off the tumor’s ability to hide from the immune system and simultaneously switches on the immune system’s capacity to attack cancer. The tiny nanoparticle-turned-immunoswitch is 1,000 times smaller than the diameter of a hair but has the potential to cause a big improvement in the effectiveness of a type of combination immunotherapy involving checkpoint inhibitors, drugs that shut down the cancer’s ability to evade the immune system. In animal models of melanoma, the nanoparticle immunoswitch significantly reduced the size of tumors and increased survival.
New Treatment Combo: A new treatment approach aims to make currently incurable pancreatic cancers curable. About 40 percent of pancreatic cancer patients are diagnosed when the cancer has begun to attach itself to tissue and vessels around the pancreas, so not all patients are candidates for surgery. Valerie Lee, M.D., is collaborating with Elizabeth Jaffee, M.D., the Dana and Albert “Cubby” Broccoli Professor in Oncology, Daniel Laheru, M.D., the Ian T. MacMillan Professor of Clinical Pancreatic Cancer Research, and Lei Zheng, M.D., Ph.D., to use a combined approach to get more patients to surgery. It involves standard anticancer drugs to stabilize the cancer, followed by a pancreatic cancer vaccine and an immune check- point inhibitor. Lastly, patients will receive stereotactic radiation therapy. The investigators believe the combination therapy will kill cancer cells outright and also awaken the immune system to go after the cancer. If it works, patients would then have surgery, chemotherapy and more immunotherapy.
Turning Up the Heat on Breast Cancer: In certain types of breast cancer, the presence of T cells may predict a response to immunotherapy. Tumors that have few or no T cells are called “cold” because they are unlikely to respond to immunotherapy. Tumors with lots of T cells poised for response are called “hot.” Leisha Emens, M.D., Ph.D., and Drew Pardoll, M.D., Ph.D., the Martin D. Abeloff Professor, are using an animal model to study an injectable drug that may convert cold tumors into hot tumors. The drug activates STING (stimulator of interferon genes) signaling and causes T cells to traffic to the tumor, making breast cancer cells more responsive to immune checkpoint inhibitors, like anti-PD-1.
Prostate Cancer Immune Booster: A testosterone-lowering prostate cancer drug called degarelix appears to also stimulate an immune attack against the cancer. The finding builds upon 2005 animal studies that showed that reducing testosterone brought cancer-fighting immune T cells into the prostate. Prostate cancer expert Emmanuel Antonarakis, M.B.B.Ch., and pathologist Angelo De Marzo, M.D., Ph.D., studied the drug alone and in combination with other immunotherapies in men who were scheduled to have a radical prostatectomy to remove their cancerous prostate glands. They found that the most important factor in stimulating T cells in the prostate was degarelix. Unfortunately, the drug simultaneously activated cells that dampen the immune response. Future trials will explore combined therapies that protect the immune-stimulating benefits of the drug but interfere with its immune-dampening effects.
Leukemia and Lymphoma
Studying Immunotherapy in Virus-Associated Cancer: A new study, led by Richard Ambinder, M.D., Ph.D., the James B. Murphy Professor in Oncology, examines the benefits and potential side effects of the anti-PD-1 immunotherapy drug nivolumab in T-cell leukemia-lymphoma virus (HTLV-1)-associated leukemia and lymphoma. The study focuses on HTLV-1-infected leukemia and lymphoma patients for which no standard therapy is available and those who have not responded to chemotherapy, radiation therapy or other treatments.
Head and Neck Cancer
Using Genomic and Immunological factors to improve Immunotherapy for head and neck cancers: Analyzing the genetic and immune landscapes of head and neck tumors can predict responsiveness to cancer immunotherapy, and guide rationale combinations in order to increase benefit from such treatments for patients with head and neck cancer.
To better understand the diverse patterns of patient clinical response, we are actively investigating the precise characteristics of individual patients’ tumors including tumor mutational/neoantigen burden, single cell/global gene expression, and immune intrinsic/extrinsic exhaustion profiles in response to anti-PD-1 therapy as well as multiple novel combinations.
One particular focus of the team around head and neck surgeons Raj Mandal, Carole Fakhry and medical oncologist Tanguy Seiwert, are patients with potentially curative disease where immunotherapy is given before curative treatment, and resulting treatment effects can be studied in much more detail, allowing in depth profiling of the effects of novel combinations. However, understanding of tumor immune escape mechanisms may ultimately be broadly applicable including also for recurrent or refractory disease, where there still is an urgent need for better therapies.
In order accomplish this we employ innovative model systems such as Patient-Derived Organoid (PDO) and Histoculture Bioreactors .
Our aim is to better understand the complex immune escape mechanisms including the contribution of myeloid. Collectively, this knowledge will ultimately help us better personalize and improve efficacy of immunotherapy for patients with head and neck cancer.
Battling the Deadliest of Cancers: Stuart Grossman, M.D., and Matthias Holdhoff, M.D., Ph.D., are looking to immunotherapy to improve glioblastoma brain cancer survival. Glioblastoma is the most common brain cancer in adults, but has dismal survival rates. Despite hundreds of clinical trials of new drugs, few have extended survival. As the headquarters for the National Brain Tumor Alliance and home to the Bloomberg~Kimmel Institute, our researchers will begin to explore immunotherapy as a new treatment option.
CAR-T Therapy Trial: The Kimmel Cancer Center Pediatric Oncology Division is one of just two-dozen cancer centers providing a type of CAR-T therapy for children and young adults with resistant or relapsed B-lymphoblastic leukemia. Patrick Brown, M.D., is leading this treatment program. CAR-T, or chimeric antigen receptor therapy, removes patients’ own immune cells and returns them in large numbers armed with new proteins that allow them to recognize cancer.
Most patients who receive immune-based cancer treatments do so as part of a clinical trial. Recently, the FDA has approved some immune therapies for certain types and stages of cancer. Johns Hopkins offers access to a range of clinical trials for many different cancer types.
In addition to testing the effectiveness of certain drugs or treatment protocols, a major goal of our clinical researchers and nurses is to partner with patients to gather information that will help them better understand how different immune therapies affect different individuals, or groups of individuals.
Smaller, investigator-led trials could help bring therapies to patients sooner
Scientists in the Bloomberg~Kimmel Institute for Cancer Immunotherapy lead clinical trials that, in many cases, began as ideas in laboratories at Johns Hopkins.
These investigator-initiated trials are smaller, which means they can move more efficiently through the phases of clinical development and potentially benefit more patients sooner. These trials also allow physician-scientists more flexibility to explore new applications for drugs that have already been proven safe and effective, whether in new dosages or combinations, or on different types or stages of cancer.
Could an immunotherapy clinical trial be right for you? Make an appointment for a consultation by calling the Kimmel Cancer Center’s appointment line at 410-955-8964.
Find a clinical trial
View a complete listing of clinical trials offered at the Johns Hopkins Kimmel Cancer Center.