The Bloomberg~Kimmel Institute for Cancer Immunotherapy

Our researchers are collaborating with experts in the Johns Hopkins Greenberg Bladder Cancer Institute on new immunotherapies. We are exploring whether heightening immune surveillance using the FDA-approved drug pembrolizumab (Keytruda), an anti-PD-1 therapy, improves the treatment of bladder cancer that has invaded the muscle wall of the bladder. We are combining the drug with radiation therapy and the chemotherapy drug gemcitabine with the goal of engaging the immune system to stop the growth of the tumor and the spread of bladder cancer cells to other parts of the body. The FDA approved pembrolizumab (Keytruda) for any cancer with a genetic trait called microsatellite instability, occurring in about four percent of all advanced cancers. As part of your personalized treatment plan, our experts may test your cancer for this genetic trait.

More information on bladder cancer clinical trials:

• Cancer.gov
• Kimmel Cancer Center

As the headquarters for the National Brain Tumor Alliance and home to the Bloomberg~Kimmel Institute, our doctors are looking to immunotherapy to improve brain cancer survival. Glioblastoma is the most common brain cancer in adults, but despite hundreds of clinical trials of new drugs, few have extended survival. Researchers continue to study immune cell-boosting drugs in the laboratory to develop better treatments for glioblastoma.

More on clinical trials:

• Cancer.gov
• Kimmel Cancer Center

Our experts are leading studies of anti-PD-1 immunotherapies in breast cancer, a treatment that tears down a shield that hides cancer from the immune system. Several anti-PD-1 drugs are now FDA approved for cancer treatment. In certain types of breast cancer, the presence of T cells may predict a response to immunotherapy. Our experts are using an injectable drug to cause T cells to traffic to tumors and make breast cancer cells more responsive to treatment with immune checkpoint inhibitors, like anti-PD-1.

Researchers are also exploring cells in and around breast tumors that may influence the immune response. Drugs called epigenetic-targeted therapies may help prime the immune system to attack breast cancer and help immunotherapies, like anti-PD-1 work better. Other drugs that go after other targets that work as on and off switches for T cells are being tested in combination with immunotherapy. Our doctors are also exploring cancer vaccines that can be used for breast cancer. The FDA approved pembrolizumab (Keytruda) for any cancer with a genetic trait called microsatellite instability, occurring in about four percent of all advanced cancers. As part of your personalized treatment plan, our experts may test your cancer for this genetic trait.

Read Breast Matters immunotherapy issue.

More on clinical trials:

• Cancer.gov
• Kimmel Cancer Center

The FDA approved pembrolizumab (Keytruda) for colon cancer and other cancers with a genetic trait called microsatellite instability, occurring in about four percent of all advanced cancers. As part of your personalized treatment plan, our experts may test your cancer for this genetic trait. One of our colon cancer experts led the clinical trial that resulted in the FDA approval of the drug. Other clinical studies explore using the FDA-approved drug 5-azacytadine to prime cancer cells to respond better to immunotherapy.

More on clinical trials:

• Cancer.gov
• Kimmel Cancer Center

A new experimental type of personalized cell immunotherapy, developed by a Bloomberg~Kimmel Institute doctor, is being explored as a treatment for esophageal cancer. The treatment involves collecting cancer-attacking immune cells, called marrow infiltrating lymphocytes or MILs, from the patient’s bone marrow, then expanding the number of these cells in a special Cell Therapy Lab before returning them to the patient by IV where they travel through the bloodstream to seek out and destroy cancer cells. Our doctors are also exploring whether combining radiosurgery with immunotherapy may work better against the cancer and if immunotherapy before surgery will activate the immune system to begin attacking tumors. The FDA approved pembrolizumab (Keytruda) for any cancer with a genetic trait called microsatellite instability, occurring in about four percent of all advanced cancers. As part of your personalized treatment plan, our experts may test your cancer for this genetic trait.

Patients diagnosed with head and neck squamous cell cancer that has come back after treatment, stopped responding to chemotherapy, or spread may be treated with the FDA-approved immunotherapy pembrolizumab (Keytruda). The immunotherapy nivolumab (Opdivo) is also approved for squamous cell head and neck cancer. Current or former smokers diagnosed with head and neck cancer may also respond well to immunotherapy because their tumors often have high numbers of gene mutations that attract immune cells. Another type of cancer, called human papillomavirus (HPV)-associated head-and-neck cancer, may also respond well to immunotherapy because the HPV virus is only expressed in tumor cells. Researchers are developing ways to get the immune system to eliminate the cancer by attacking the virus. Personalized cell therapy is also being developed for patients with head and neck cancer. The FDA has also approved pembrolizumab (Keytruda) for any cancer with a genetic trait called microsatellite instability, occurring in about four percent of all advanced cancers. As part of your personalized treatment plan, our experts may test your cancer for this genetic trait.

More on clinical trials:

• Cancer.gov
• Kimmel Cancer Center

Kidney (renal cell) cancer was among the first cancers that responded to immunotherapy. Patients with advanced kidney cancer may be treated with the FDA-approved immunotherapy nivolumab (Opdivo), an anti-PD-1 therapy. Immunotherapy drugs alpha-interferon and interleukin-2 are also used to treat some types of kidney cancer. The Bloomberg~Kimmel Institute is participating in a multi-center clinical trial testing a drug called CPI-444 in kidney cancer.

More on clinical trials:

• Cancer.gov
• Kimmel Cancer Center

The immunotherapy drug pembrolizumab (Keytruda), an anti-PD-1 drug, is FDA approved for adult and pediatric patients with Hodgkin lymphoma whose cancer did not respond to standard treatment or has returned after standard therapies. Nivolumab (Opdivo) has also been FDA approved for some patients with Hodgkin lymphoma. Bone marrow transplant, including the haploidentical type pioneered by Kimmel Cancer Center scientists, is approved to treat many types of leukemia and lymphoma in adults and children. The Kimmel Cancer Center is also a CAR-T therapy (Kymriah) site for children and young adults with resistant or relapsed B-lymphoblastic leukemia and for adults with several types of relapsed and treatment- resistant non-Hodgkin lymphoma.

More on clinical trials:

• Adult Leukemia: Cancer.gov
• Lymphoma: Kimmel Cancer Center

New and better treatments for liver cancer is a focus of the Bloomberg~Kimmel Institute’s Rare Malignancies Program. One approach being studied involves the anti-PD-1 immunotherapy drug, nivolumab (Opdivo), and another gene-targeted drug, called cabozantinib. A clinical trial is planned to study if combining the two drugs will prove to be even more effective against the cancer than either drug alone. The FDA approved pembrolizumab (Keytruda) for any cancer with a genetic trait called microsatellite instability, occurring in about four percent of all advanced cancers. As part of your personalized treatment plan, our experts may test your cancer for this genetic trait.

The Nivolumab (Opdivo) is FDA-approved for treatment of advanced non-small-cell lung cancer in patients whose cancers progress on standard therapy. Pembrolizumab (Keytruda) became the first immunotherapy to gain FDA approval as the front line treatment for non-small-cell lung cancer patients whose cancer cells have a lot of PD-L1 protein. All other immunotherapies are approved as a secondary option for patients whose cancers have not responded to chemotherapy. Our experts led the clinical trials that produced the data used to earn the FDA approvals.

Most of today’s immunotherapy breakthroughs are built upon melanoma research that began nearly 30 years ago, when it was realized that the immune system can vigorously react to melanoma.

Immunotherapy is a broad term for treatments that stimulate a patient’s immune system to attack cancer cells. This treatment strategy should be part of the conversation for most patients with advanced skin cancers, although it may not be appropriate for every patient.

Immune Checkpoint Blockers

Immune checkpoint blockers interfere with signals cancer cells use to hide from immune cells. Sometimes, cutting off the inhibitory signals transmitted from cancer cells to immune cells can unleash an immune attack against the cancer. This may require treatment with a single checkpoint blocker or a combination of two or three different checkpoint blockers. Immune checkpoints can be thought of as traffic lights for immune cells, regulating when they stop and when they go. Different checkpoint blockers control different traffic lights. For some cancers, it may take just one checkpoint blocker to give the green light to immune cells. For other cancers, it may take two or three checkpoint blockers to clear the way for immune cells to attack cancer cells.

PD-1 Blockers

The drugs nivolumab (Opdivo) and pembrolizumab (Keytruda) block the PD-1 checkpoint expressed on immune cells trying to attack cancer cells. Much of the science behind these drugs was developed at Johns Hopkins and has revolutionized the treatment of melanoma and other aggressive skin cancers. The first FDA approvals were for patients with advanced melanoma, and the drugs have increased long-term survival for these patients from approximately 5 percent to about 50 percent. More recently, nivolumab was FDA-approved for treating patients with stage 3 melanoma after surgery, to prevent relapse.
Ongoing laboratory research and clinical trials are exploring combinations of anti-PD-1 with other checkpoint blockers that may make the treatment work better and in even more patients. Using one or more of these other checkpoint blockers with a PD-1 checkpoint blocker can interfere with additional signals and turn red lights to green lights. These signals include KIR, IL-8, and LAG-3, all of which are the focus of ongoing clinical studies. Much of the scientific development of anti-LAG-3 occurred in laboratories in the BKI. Preliminary results from a clinical trial suggest that some melanomas that did not respond to the PD-1 checkpoint blocker nivolumab alone, responded when a LAG-3 blocker was added. Ongoing multicenter trials are investigating anti-LAG-3 plus anti-PD-1 in a variety of cancer types.

Adoptive Cell Therapy

Adoptive cell therapy is another type of immunotherapy that can be a powerful treatment for patients with melanoma. In one type of adoptive cell therapy, the patient's own tumor is taken into the laboratory so that immune cells within the tumor, called tumor-infiltrating lymphocytes, can be isolated and modified to become better cancer fighting cells. A few weeks later these cells are given back to the patient through an IV. Although this kind of immunotherapy is not yet FDA-approved in melanoma, it has been studied and tested for more than 30 years and is performed in specialized research centers.

Melanomas with BRAF Mutations

Melanomas that contain a specific type of mutation in a gene called BRAF may respond to other types of drugs, known as BRAF and MEK inhibitors. Although our experts believe that immunotherapy should be considered for most patients diagnosed with melanoma because remissions may be long-lasting, patients with BRAF-mutant melanomas and their doctors should discuss which type of treatment—PD-1 checkpoint blockers or BRAF/MEK inhibitors—should be tried first.

Advanced Basal Cell Carcinoma

As part of the Bloomberg~Kimmel Institute for Cancer Immunotherapy’s Skin Cancer Program, our experts plan to study nivolumab for patients with advanced basal cell skin cancer as a first treatment, or for patients whose cancer comes back after treatment with standard therapy (hedgehog inhibitors). Basal cell carcinoma is the most common type of skin cancer and 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. The response of basal cell carcinoma to anti-PD-1 will be studied in a new clinical trial conducted at Johns Hopkins.

Merkel Cell Cancer

Our skin cancer experts co-led a national trial and published the first study showing that a PD-1 checkpoint blocker worked in many cases of advanced Merkel cell cancer, a rare but very aggressive form of skin cancer. Before this study, it was considered an orphan disease lacking good treatment options. Our experts are building upon these initial findings, in a new study that combines nivolumab and the CTLA4 blocker ipilimumab (Yervoy) in an effort to get long-lasting responses for more patients. Research in other cancers found this combination worked well in some patients whose cancers did not respond to nivolumab alone.

Skin Cancer After Kidney Transplant

Our experts are leading a clinical trial of immunotherapy for kidney transplant recipients who develop advanced skin cancers. Kidney transplants are the most common type of solid organ transplant in the U.S., and cancer, most often resulting from the immune suppression required to prevent organ rejection, is the third most common cause of death among kidney transplant patients. Skin cancer is the most common cancer that kidney transplant patients develop. Typically, the cancers occur many years after transplant, are detected early and easily treatable. However, some transplant recipients develop advanced skin cancers. A combination of the immunotherapy nivolumab and tacrolimus, an immunosuppressant used to prevent kidney rejection, will be studied through a Bloomberg~Kimmel Institute-led multi-institutional collaboration supported by the National Institutes of Health Cancer Therapy Evaluation Program and Experimental Therapeutics Clinical Trials Network.
The combined treatment is aimed at striking a balance that will help the body’s immune system identify and kill cancer cells but leave the transplanted organ alone.

Why melanoma and other advanced skin cancers respond to immunotherapy:

Our unique collaboration between laboratory researchers and clinicians is key to our advances in immunotherapy—identifying treatments for each patient that will bring about long-lasting control of cancer.

Our research has uncovered two signs that identify a cancer that is likely to respond to immunotherapy:

1. Cancer cells that contain many mutations in their DNA
2. Cancer cells that express a protein called PD-L1

Generally, skin cancers have some of the highest number of DNA mutations among all cancers, which are caused by exposure to ultraviolet light (sunlight, or tanning beds). Many of these cancers express the PD-L1 protein. However, this is not the whole story. There are skin cancers that have lots of DNA mutations and express the PD-L1 protein but do not respond to immunotherapy. A better understanding of these two biomarkers and uncovering new ones is a major focus of ongoing research in the BKI. This will help our experts figure out how to make immunotherapy work effectively in more patients. Our experts are exploring whether cancers that start in the skin, a highly immune organ that is the first line of defense against foreign invaders, are more easily recognized by the immune system than other types of cancers.

Immunotherapy and Surgery

New research is also exploring if medical therapy given to patients with melanomas that have been removed by surgery could prevent cancers from coming back. Recent clinical trials have demonstrated that PD-1 checkpoint blockers and, in patients with BRAF-mutant melanomas, BRAF/MEK inhibitors can improve outcomes in these patients. Nivolumab and dabrafenib+trametinib were recently FDA-approved for this purpose.
Additionally, emerging research shows that anti-PD-1 immunotherapy given briefly before surgery, called neoadjuvant therapy, may also prevent cancer recurrence. Bloomberg~Kimmel Institute experts have demonstrated promising activity in a type of lung cancer called non-small cell lung cancer, and an ongoing clinical trial in Merkel cell carcinoma is also showing promise.

To make an appointment, please phone the Melanoma Coordinator at 410-616-7660.

• More information on melanoma and skin cancer clinical trials
• Cancer.gov: melanoma and other skin cancers, Merkel Cell cancer
• Kimmel Cancer Center

A type of personalized cell therapy called MILs (marrow infiltrating lymphocytes) therapy was developed at the Bloomberg~Kimmel Institute and is being studied in clinical trials as a treatment for patients with multiple myeloma, a cancer of blood plasma cells. MILs are a type of tumor-specific immune cell that recognizes cancer cells. The treatment involves collecting MILs from the patient’s bone marrow, expanding the number of these cells in a special Cell Therapy Lab before returning them to the patient by IV where they travel through the bloodstream to seek out and destroy cancer cells.

Several variations of a cancer vaccine were developed by our experts and are being studied as a treatment for patients. The vaccines are built from pancreatic cancer cells made dormant with radiation and engineered to recruit immune cells to track and attack pancreatic cancer cells. One approach involves giving the vaccine before surgery to get ahead of the cancer and kill microscopic cancer cells that surgery might miss. Another variation involves using the drug cyclophosphamide before vaccination to reprogram immune cells within the tumor and then adding an anti-PD-1 immunotherapy to further boost an immune attack against the cancer. Another approach adds a second vaccine to stimulate an immune attack against a protein found in high levels on pancreatic cancer cells followed by an anti-PD-1 drug. A combined treatment with chemotherapy first to stabilize the cancer, followed by a pancreatic cancer vaccine and anti-PD-1 immunotherapy, and lastly, stereotactic radiation therapy is also being studied.

• Read Pancreatic Cancer Matters immunotherapy issue.
• Cancer.gov
• The Skip Viragh Center for Pancreatic Cancer Clinical Research and Patient Care

The first successful immunotherapy reported in prostate cancer comes from a Bloomberg~Kimmel Institute study. Immunotherapy appears to work against prostate cancers with a resistance mutation, known as AR-V7, and clinical trials of anti-PD-1 and anti-CTLA-4 immunotherapy drugs are planned. MILs therapy, a type immunotherapy that uses cancer-specific marrow infiltrating lymphocytes to attack cancer cells, is also being explored in prostate cancer.

• Cancer.gov
• Kimmel Cancer Center

New and better treatments for stomach cancer are a focus of the Bloomberg~Kimmel Institute’s Rare Malignancies Program. Collaborating with a pharmaceutical company, our doctors plan to study immunotherapy drugs that have proven successful in other cancers. Five studies are currently planned, including one that first uses chemotherapy to decrease the size of tumors followed by treatment with anti-PD-1 immunotherapy. The FDA approved pembrolizumab (Keytruda) for any cancer with a genetic trait called microsatellite instability, occurring in about four percent of all advanced cancers. As part of your personalized treatment plan, our experts may test your cancer for this genetic trait.