New treatment strategy may thwart deadly brain tumours

New research in mice led by investigators at Massachusetts General Hospital (MGH) and the University of Florida reveals a promising strategy that makes glioblastoma susceptible to these medications. The findings, which are published in the Proceedings of the National Academy of Sciences, indicate that such combination therapy should be tested in clinical trials of patients with glioblastoma, for whom there is no known cure.

Part of the reason glioblastoma do not respond well to immune checkpoint inhibitors and other immunotherapies is because cells called myeloid-derived suppressor cells (MDSCs) infiltrate the region surrounding glioblastoma tumours, where they contribute to immunosuppression, tumour progression, and treatment resistance. Thus, targeting these cells may augment immunotherapy and improve responses to treatment in affected patients.

A collaborative effort co-led by Jeffrey K. Harrison, PhD, of the Department of Pharmacology and Therapeutics at the University of Florida, and Rakesh K. Jain, PhD, of the Department of Radiation Oncology at MGH and Harvard Medical School, set out to test this strategy.

Using two mouse models of glioblastoma, the team targeted receptors–called chemokine receptors–that are important for allowing MDSCs to infiltrate into the region surrounding glioblastoma tumours. In mice that were bred to lack chemokine receptor 2 (CCR2) and to develop glioblastoma, MDSCs could not carry out such infiltration.

Treating these mice with an immune checkpoint inhibitor stimulated a strong anti-cancer immune response and prolonged the animals’ survival. In mice with normal CCR2, treatment with a molecule that blocks CCR2 had similar effects.

According to Jain, “The CCR2 antagonist used in this study–called CCX872– has passed phase Ib safety trials in patients with pancreatic tumours, and clinical trials are ongoing to investigate the use of CCR2 inhibitors in several cancers.”

“Thus, the results of this study support targeting CCR2-expressing MDSCs as a means to enhance immunotherapies, and warrant investigation of this combination therapy in clinical trials for patients with glioblastoma,” says Jain.

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A 'safe' immunotherapy offers hope for cancer patients with HIV

A new category of immunotherapies, called checkpoint inhibitors, appears safe to use in patients with both advanced malignancies and HIV, according to a recent study.

"During the development of these drugs, people with HIV were routinely excluded from studies due to concerns that they would not tolerate these medications or perhaps not benefit from them because of their underlying HIV and associated immune dysfunction," he said. "The most important first step was to show that this class of drug would be safe in cancer patients with HIV."

Study participants, who were on standard antiretroviral therapy to control their HIV infections and had various cancers that had failed to respond to standard therapies, received pembrolizumab (Keytruda), known since 2015 as "the Jimmy Carter drug" after it swiftly beat back melanoma that had spread to the former president's brain and liver.

"These drugs are the backbone of cancer immunotherapy at present and have been shown to be effective in subsets of virtually every different kind of cancer," said senior author. "For patients with HIV who are using effective antiretroviral therapy and have cancers for which these drugs are approved, there's no reason not to consider these drugs as standard therapy."

From the earliest days of the AIDS pandemic, Kaposi sarcoma -- a rarely seen cancer until then -- was one of a trio of cancers known as AIDS-defining malignancies. It, non-Hodgkin lymphoma and, in women, cervical cancer, often signaled that a person's HIV infection had progressed to full-blown AIDS. People did not die of AIDS, per se. They died of one of these cancers or of infections like pneumocystis pneumonia and toxoplasmosis that took advantage of a weakened immune system.
The ongoing study will enroll up to 36 patients, and there are plans to include more patients with Kaposi sarcoma, a cancer for which checkpoint inhibitors have not been studied. It is one of the leading causes of cancer deaths in sub-Saharan Africa -- where HIV rates are high -- and new treatments are sorely needed.

Also to be presented Friday is the death of one patient later in the study who had Kaposi sarcoma. The death is still being evaluated but was likely due to dissemination of KSHV. Uldrick and Cheever said review of the case suggests the patient had a history of symptomatic KSHV viremia, and the study has been changed to exclude such patients in the future and provide specific guidelines for management should new symptomatic KSHV viremia be observed.

Six other study participants with Kaposi sarcoma or primary effusion lymphoma have been treated on this study. None has experienced similar problems, and some have benefitted from therapy, Dr. said.

"We do not believe that this takes away from the safety message in patients with HIV and other, better studied cancers," Dr. said. "However, more experience is clearly needed in treating KSHV-associated diseases with checkpoint inhibitors."
 

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