Immune System-Boosting "Immune Checkpoint Inhibitors" Show Promise for Treating Many Kinds of Cancer

The gist: Drugs called “immune checkpoint inhibitors” have shown promise for patients with multiple types of cancer. Immune checkpoint inhibitors are a type of immunotherapy, meaning they boost a patient’s own immune system to fight cancer. Two particularly promising immune checkpoint inhibitor drugs are MPDL3280A and pembrolizumab.

“Treatment with an immune checkpoint inhibitor led to consistent responses across multiple types of cancer, particularly in patients with suppressed immune systems that appeared to be ‘reinvigorated’ by the therapy, investigators reported.

“Response rates of 20% to 25% were seen in patients with advanced cancers, including lung, kidney, and head and neck cancers, as well as melanoma. The overall response to the engineered antibody MPDL3280A increased to 46% in patients whose tumors exhibited overexpression of programmed death-ligand 1 (PD-L1), a protein associated with immune suppression in multiple types of cancer, as reported a research letter in Nature.

“The antitumor activity was encouraging, but the identification of markers predictive of response could prove to be equally important if not more so, according to Roy S. Herbst, MD, PhD, of the Yale Cancer Center.

” ‘The most compelling thing about the study is the fact that we worked to develop predictive markers for who responds and who doesn’t,’ Herbst told MedPage Today. ‘We can measure PD-L1 immunostaining in the immune infiltrate — not on the tumor cells but on the macrophages and the lymphocytes in the immune microenvironment.’ “


Early Trial of New Drug Shows Promise for Patients with Triple-Negative Breast Cancer

The gist: A drug called pembrolizumab (aka Keytruda or MK-3475) has shown promise for people with metastatic triple-negative breast cancer (TNBC) whose tumors have high levels of a protein called PD-L1.  It was recently tested in patients in a clinical trialPembrolizumab is already approved by the U.S. Food and Drug Administration (FDA) for treating melanoma. It is an immunotherapy, meaning that it boosts a patient’s own immune system to fight cancer. More research will determine just how well pembrolizumab might work for TNBC.

“In patients with metastatic triple-negative breast cancer—a disease with no approved targeted therapies—infusion of pembrolizumab produced durable responses in almost one out of five patients enrolled in a phase-Ib clinical trial, according to data presented Dec. 10, at the 2014 San Antonio Breast Cancer Symposium.

“The multi-center, non-randomized trial was designed to evaluate the safety, tolerability and antitumor activity of bi-weekly infusions of pembrolizumab (MK-3475, marketed as Keytruda®). The researchers enrolled 27 patients, aged 29 to 72 years, who had metastatic triple-negative breast cancer that either relapsed after treatment for early stage disease or progressed on therapy for advanced disease.

” ‘For this group of patients our treatment options are limited to chemotherapy,’ said study director Rita Nanda, MD, assistant professor of medicine and associate director of the breast medical oncology program at the University of Chicago.

“All patients in the study had triple-negative tumors with high levels of a protein called programmed death-ligand 1 (PD-L1). This protein can suppress the immune system’s efforts to eliminate cancer cells. Pembrolizumab is a monoclonal antibody designed to help reactivate a person’s own immune system to help fight the tumor.”


Immune System-Activating Drugs in Combination Treatments May Be Next Big Thing for Melanoma


Among solid tumors, the curative potential of immunotherapies has been explored most in melanoma. One reason for this is that melanoma tumors often contain so-called immune infiltrates—patches of T cells, the killer cells of the immune system. It seems that these fighter cells arrive at the ‘battlefield’ to target tumor cells for killing, but instead become ‘frozen,’ unable to attack.  How to activate the tumor-killing potential of T cells has been an area of intense and fruitful research, leading to the development of several immunotherapy drugs. Continue reading…


Immune System-Boosting Drugs, New and Old, Are Explored in Combination Treatments for Lung Cancer


Readers of this blog will already know a thing or two about immunotherapy (immune system-activating drugs) and targeted therapy in lung cancer. Both approaches have benefited many patients in recent years. Now, research is being done to combine immunotherapies with other types of drugs. Of particular interest are immunotherapies that target PD-1, PD-L1, and CTLA4. These drugs, also known as immune checkpoint antibodies, are being tested in combination with other drugs in patients participating in the clinical trials below. Continue reading…


Failed Cancer Vaccines Might Live Again with New Immune Drugs

“Using vaccines to fight cancer is a field littered with failures but experts believe it is possible the approach could get a new lease of life if such shots are combined with a new class of drugs called checkpoint inhibitors.

“Unlike traditional preventative vaccines, therapeutic cancer vaccines are designed for people with established disease and are supposed to boost the patient’s immune system to keep tumors at bay.

“Unfortunately, the theory has not worked out in practice because, while the vaccines are successful at triggering a response from the ‘foot soldiers’ of the immune system, cancer cells still manage to escape detection.

“The result has been a series of failures with high-profile experimental cancer vaccines such as Merck KGaA’s Stimuvax and GlaxoSmithKline’s MAGE-A3.

“GSK threw in the towel on its vaccine in April, dashing hopes for a project that was once seen as a potential multibillion-dollar sales opportunity in lung cancer and melanoma.”


Studies Report New Findings on Treatment Options for Mesothelioma

The gist: This article discusses new findings for mesothelioma treatment from two research studies. The first study was a clinical trial—a research study with volunteer patients. The researchers found that people with malignant pleural mesothelioma who have been treated with chemotherapy and surgery unfortunately do NOT benefit from further treatment with high-dose radiation therapy. The second study was more promising. It found that 20% of people with malignant pleural mesothelioma have cancer cells that express the immune system protein PD-L1. This is important because immunotherapy drugs have already been developed to fight cancers that express PD-L1, such as other forms of lung cancer and melanoma. Clinical trials may soon test whether mesothelioma patients could benefit from anti-PD-L1 drugs.

“Treating patients with high-dose radiotherapy after chemotherapy and surgery for malignant pleural mesothelioma does not achieve improvements in local relapse and overall survival, according to data from a prospective randomized phase II trial presented at ESMO 2014 Congress in Madrid.

” ‘Mesothelioma remains a difficult disease to find better treatment options for, so we asked whether high-dose hemithoracic radiotherapy would decrease the rate or delay the time of local recurrence after chemotherapy and radical surgery,’ says lead author Prof Rolf A. Stahel, from the Clinic and Policlinic for Oncology, at the University Hospital Zurich, Switzerland, and current President of the European Society for Medical Oncology.

“The multicentre trial included 153 patients with surgically-treatable malignant pleural mesothelioma, who were first treated with three chemotherapy cycles of cisplatin and pemetrexed, followed by surgical removal of affected lung tissue, with the goal of complete removal of the cancerous areas of lung.”


Cancer Immunotherapy on the Cusp

Editor’s note: Immunotherapy is a type of cancer treatment that uses a patient’s own immune system to fight cancer. Immunotherapies work in multiple types of cancer, but they have been particularly successful in treating melanoma. This article gives a good overview of the current state of immunotherapy research.

“Glass crystals with thread-like filaments floating inside sit in the offices of two prominent immunologists. The clear blocks encase models of the structure of PD-1/PD-L1, a receptor-ligand pair that rides on the surface of cells, ready to rein in the immune system after its work attacking invaders is done.

“PD-1 looms large in the growing field of cancer immunotherapy, which is why one model appears on Gordon Freeman’s desk in the Dana-Farber Cancer Institute and the other in Arlene Sharpe’s office at Harvard Medical School. Their basic science discoveries about how cancer cells hijack PD-1 to turn off the immune system are being translated into therapies that they hope and believe can change cancer treatment. After 15 years, drugs developed by several pharmaceutical companies based on the scientists’ work are awaiting approval by the U.S. Food and Drug Administration.

” ‘It’s coming,’ Freeman, HMS associate professor of medicine at Dana-Farber, said this summer, anticipating FDA action.”


AstraZeneca Widens Cancer Immunotherapy Net with Advaxis Trial

The gist: Cancer treatments called immunotherapies, which boost a patient’s own immune system to fight cancer, are currently a very active focus of research for drug companies. Two drug companies have now decided to collaborate and combine their two immunotherapy drugs to see how well they work for people with HPV-associated cervical cancer or head and neck cancer. The two companies will jointly run a clinical trial with volunteer patients to test the combination treatment, in the hope that the combo will work better than either drug alone. The drugs being combined are MEDI4736 and ADXS-HPV.

“AstraZeneca is casting its net wider in the hot cancer immunotherapy field through a clinical trial collaboration with U.S. biotech firm Advaxis that will test drugs from both companies in combination.

“Britain-based AstraZeneca – the target of an unsuccessful $118 billion takeover bid by Pfizer earlier this year – is banking on widespread use of its immunotherapy drugs, which boost the body’s immune system, to fight a range of tumours.

“Under the deal with Advaxis, its so-called anti-PD-L1 drug MEDI4736 will be evaluated in a Phase I/II clinical study together with the U.S. company’s cancer vaccine ADXS-HPV in patients with human papillomavirus (HPV)-associated cervical cancer and HPV-associated head and neck cancer.”


Targets for Immunotherapy in Early-Stage Breast Cancer

The gist: Treatments called immunotherapies, which boost a patient’s own immune system to fight cancer, are an exciting area of cancer research. One kind of immunotherapy drug works by targeting a specific protein called PD-L1, which can help tumors evade immune system attack. Oncologists can figure out whether an anti-PD-L1 immunotherapy drug might work for a patient based on the amount of PD-L1 protein found in a tumor, but PD-L1 levels can be difficult to accurately detect. Researchers have now developed a new, better test to measure PD-L1 levels in early-stage breast cancer tumors. Anti-PD-L1 drugs are currently being tested in clinical trials with volunteer advanced breast cancer patients, and anti-PD-L1 drugs may soon also be tried in early-stage breast cancer patients.

“Yale Cancer Center researchers used a new molecular analysis tool to accurately detect the level of an important target for immunotherapy in early-stage breast cancers. The diagnostic test, using RNAScope, measures the amount of PD-L1 (programmed death ligand 1) mRNA in routine formalin-fixed cancer tissues and is devoid of many of the technical issues that plague antibody-based detection methods that have yielded conflicting results in the past. PD-L1 is the target of several novel immune stimulatory therapies in clinical trials. The findings were published in the Journal of Clinical Cancer Research in May.

“PD-L1 is a protein that plays an important role in suppressing immune response, and in cancer, it may allow tumors to evade immune attack. The study demonstrated that about 60 percent of early-stage breast cancers have PD-L1 expression, and a subset of these cancers also have large numbers of tumor infiltrating lymphocytes. High levels of lymphocytes and PD-L1 predicted for better survival, suggesting a beneficial role for the immune system in at least partially controlling these cancers.

” ‘This is exciting because these findings provide the rationale to test PD-L1 targeted therapies in breast cancer with the hope of further improving cure rates in early stage breast cancer,’ said Lajos Pusztai, MD, DPhil, professor of Medical Oncology and chief of Breast Medical Oncology at Smilow Cancer Hospital, Yale Cancer Center, and an author on the study. ‘Patients with many tumor infiltrating lymphocytes and high PD-L1 expression may be the ideal candidates for these therapies.’ “