BKI Research: Making
Waves, Improving Lives
How Mismatch Repair Deficient Cancers Signal The Immune System
Immunotherapy and checkpoint inhibitor drugs have emerged as a success story in the treatment of cancer — in particular for patients with a DNA spell-checklike error known as mismatch repair (MMR) deficiency. Indeed, the effectiveness of immunotherapy led to an historic FDA approval of pembrolizumab, the first-ever cancer drug approval that was not specific to a particular cancer type. Still, for about half of patients with mismatch repair deficiency, immunotherapy did not prove effective. Now, in new research published in Science, the Bloomberg~Kimmel Institute for Cancer Immunotherapy has uncovered why. Researchers discovered that there are varying degrees of MMR deficiency, and that those with the highest numbers of mutations are, in fact, the best responders to immunotherapy.
The intensity of MMR deficiency can be thought of like a volume control. Tumors that have the most intense form send the loudest signals to the immune system, and that signal weakens as the intensity of the MMR deficiency is decreased, making it not as easily recognized by the immune system.
- Dung Le, M.D., Bloomberg~Kimmel Institute investigator
Bloomberg~Kimmel Institute for Cancer Immunotherapy researchers are working now to confirm these findings in larger studies. Once verified, they’ll turn attention to developing a biomarker to evaluate the intensity of MMR-deficient cells to help identify which patients would benefit most from checkpoint inhibitor immunotherapy drugs. They will also look at ways to increase the “volume” in lower intensity mismatch repair cancers and nudge the immune system to go after the 50% of mismatch repair deficient cancers that currently do not respond.
Immunotherapy treatment with checkpoint inhibitors works by boosting the immune system’s ability to fight a cancerous tumor by taking the “brakes” off of immune cells, allowing them to attack cancer cells.
The Bloomberg~Kimmel Institute for Cancer Immunotherapy was instrumental in developing this form of treatment in MMR-deficient cancers, which tend to have a large number of mutations. These unusually large numbers of mutations distinguish normal cells from cancer cells and make the cancer visible to the immune system. As a result, these cancers — even in advanced stages — respond well to immunotherapy with checkpoint inhibitors.
Making News and Leading the Way
5 Discoveries That Put Our Researchers Ahead Of The Pack
Researchers from the Bloomberg~Kimmel Institute for Cancer Immunotherapy made a splash at the annual meeting of the American Society of Clinical Oncology (ASCO), May 31 – June 3, in Chicago. Here are the important clinical discoveries they spoke about:
ASCO is the world’s leading professional organization for physicians and oncology professionals caring for people with cancer.
1. Biomarkers Guide Immunotherapy for Melanoma
Cancer immunotherapies have made a significant impact on the treatment of melanoma, providing long-lasting responses in many patients, including those with advanced disease. Suzanne Topalian, M.D., associate director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy, reported on new biomarkers she and her colleagues are developing to guide treatment. These tests help identify melanoma patients who will benefit from treatment with immunotherapy.
2. Immunotherapy for Advanced Basal Cell Skin Cancer
The most common type of skin cancer, basal cell carcinoma, is usually cured with a simple procedure performed in a dermatologist’s office. But in a small number of patients, the cancer advances and/or spreads to other organs. Standard treatments for these advanced cases may have unpleasant side effects and generally don’t result in long-lasting responses. Bloomberg~Kimmel Institute for Cancer Immunotherapy investigator Julie Stein, M.D., reported on a study of nivolumab alone and in combination with ipilimumab for patients with advanced basal cell skin cancer as a first treatment, or for patients whose cancer comes back after treatment with standard therapy.
3. Immunotherapy Before Lung Cancer Surgery Confirmed
Surgery is viewed as a cure for many patients with non-small cell lung cancer, the most common type of lung cancer. But, tragically, most patients’ cancer recurs after surgery, and they die. Immunotherapy with checkpoint inhibitors given before surgery has been shown to shrink tumors and prevent the cancer from coming back after surgery. In the first long-term follow-up study of patients receiving this therapy, Bloomberg~Kimmel Institute for Cancer Immunotherapy investigators Drew Pardoll, M.D., Ph.D., director; Julie Brahmer, M.D., director of the BKI lung cancer program; Patrick Forde, M.B.B.Ch.; JiaJia Zhang, M.P.H.; Kellie Smith, Ph.D.; Valsamo Anagnostou, M.D., Ph.D.; and ASCO Young Investigator Award winner Joshua Reuss, M.D., confirmed survival benefits.
4. More Mutations Equals Better Responses to Immunotherapy
Tumor mutational burden (TMB) of the number of mutations within a cancer’s DNA is a biomarker for response to immunotherapy. Bloomberg~Kimmel Institute for Cancer Immunotherapy researchers previously reported that cancers with a high TMB respond best to immunotherapy drugs, even creating a tool doctors can use to measure tumor mutational burden. Now, Arsen Osipov, M.D., reported on a new study that builds upon these findings. Across 30 major solid tumor types, the research showed that patients with a higher TMB responded more strongly to treatment with a single immunotherapy drug and combined immunotherapy.
MOST IMMUNOTHERAPY PATIENTS LIVING LONGER AND BETTER
Immunotherapy has rapidly become mainstream treatment, and much of this progress has been based on work coming from the Bloomberg~Kimmel Institute for Cancer Immunotherapy. Since the first checkpoint inhibitor drug approval in 2011, patients have done so well that there has been a significant decline in cancer patients being discharged to hospice. Most patients have long lasting responses and continue to do well, but a small percentage relapse (21%) and may need additional care.
We need more data to predict who is most likely to benefit from further cancer therapy.
- Jonathan Yeh, M.D., senior assistant resident at Bloomberg~Kimmel Institute for Cancer Immunotherapy
5. Hope for Brain Cancer Patients
Brain cancer is among the deadliest cancers. Even when it responds at first to standard treatments of surgery, radiation and chemotherapy, it almost always returns. The promising results of immunotherapy among other cancer types has stimulated new research for brain cancer. Brain tumor expert Michael Lim, M.D., reported on new immunotherapy studies in a difficult-to-treat type of brain cancer known as glioblastoma. He studied three immunotherapy drugs (anti- PD-1, anti-LAG-3 and anti-CD137), alone and in combination, in patients with glioblastoma that recurs after standard treatments.
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