Enhancing immune checkpoint inhibitor therapy using treatment combination

September 5, 2018, The Wistar Institute
Credit: The Wistar Institute

A combination of a novel inhibitor of the protein CK2 (Casein kinase 2) and an immune checkpoint inhibitor has dramatically greater antitumor activity than either inhibitor alone, according to research from The Wistar Institute that was published online in Cancer Research.

Immune inhibitors have been approved to treat several types of , including some types of lung cancer and colon cancer, but not all patients who receive these immunotherapeutics gain benefit from them. A better understanding of the molecular reasons why some patients do not respond to immune checkpoint inhibitors could identify new therapeutic targets for combination treatments that may improve clinical outcomes.

"A population of immune cells called myeloid-derived suppressor cells (MDSC) has been implicated in tumor resistance to various types of cancer treatment, including immune checkpoint inhibitors," said lead researcher Dmitry I. Gabrilovich, M.D., Ph.D., Christopher M. Davis Professor and program leader of the Immunology, Microenvironment & Metastasis Program at Wistar. "We have previously shown that accumulation of the most abundant type of MDSC, polymorphonuclear MDSC (PMN-MDSC), is caused by downregulation of Notch signaling, in part as a result of CK2 activity."

Based on these previous results, Gabrilovich and collaborators set out to investigate whether combining inhibitors of CK2 with immune checkpoint inhibitors could improve immune responses in mouse models of cancer and to determine what mechanisms of action caused the results they obtained.

"Our new data suggest that using a CK2 inhibitor to manipulate the tumor microenvironment may sensitize patients to the effect of an immune checkpoint inhibitor and thereby improve clinical outcomes, although this needs to be tested in clinical trials," said Ayumi Hashimoto, a postdoctoral fellow in the Gabrilovich Lab and first author on the paper.

The researchers found that a combination of the CK2 inhibitor BMS-595 and the anti-CTLA-4-mIgG2a had antitumor activity in three different mouse models of cancer: a lung cancer, a colon cancer, and a lymphoma model. More than 60 percent of mice who received the combination treatment completely eliminated the tumor while none of the mice that received either single agent alone completely eliminated the tumor.

The mechanism of the effect of BMS-595 was analyzed, and in-depth studies showed that two of the main types of immune cells affected by the CK2 inhibitor in tumor-bearing mice were PMN-MDSCs and another type of myeloid cell called tumor-associated macrophages (TAMs). The frequency of PMN-MDSCs was not significantly altered in tumors, but it was substantially decreased in the spleen, an organ that is a part of the immune system. TAMs were decreased in the tumor.

"Our study shows that CK2 inhibition blocks the differentiation of PMN-MDSCs and TAMs, meaning that it blocked the generation of these cells from their precursors. This led to a decrease in immunosuppressive PMN-MDSCs and -promoting TAMs and thus to a substantial augmentation of the antitumor activity of immune checkpoint blockade," added Gabrilovich.

Explore further: Cellular network identified that 'short circuits' the antitumor effect of immunotherapies

More information: Ayumi Hashimoto et al, Inhibition of casein kinase 2 disrupts differentiation of myeloid cells in cancer and enhances the efficacy of immunotherapy in mice, Cancer Research (2018). DOI: 10.1158/0008-5472.CAN-18-1229

Related Stories

Cellular network identified that 'short circuits' the antitumor effect of immunotherapies

November 13, 2017
Researchers from The Wistar Institute discovered a novel form of crosstalk among tumor cells and other cell types in the tumor microenvironment, elucidating the mechanism of action of an immunotherapeutic strategy that inhibits ...

Preclinical results support entinostat's role in targeting the tumor microenvironment

July 11, 2017
Syndax Pharmaceuticals, a clinical stage biopharmaceutical company developing entinostat and SNDX-6352 in multiple cancer indications, in collaboration with The Wistar Institute and Indiana University Melvin and Bren Simon ...

Novel compound restores immune response in patients with melanoma

December 8, 2017
A novel compound may restore immune response in patients with melanoma, according to a study presented at the ESMO Immuno Oncology Congress 2017.

Scientists show how cancerous cells evade a potent targeted therapy

February 16, 2016
Imagine developing a drug designed to inhibit a protein that helps cancer cells proliferate and survive only to find that the drug does not perform very well in the clinic. This was the dilemma faced by scientists researching ...

Turning off protein could boost immunotherapy effectiveness on cancer tumors

July 31, 2018
Researchers at the Bloomberg~Kimmel Institute for Cancer Immunotherapy in the Johns Hopkins Kimmel Cancer Center discovered inhibiting a previously known protein could reduce tumor burdens and enhance the effectiveness of ...

Soluble antibodies play immune suppressive role in tumor progression

April 12, 2018
Wistar researchers have found that soluble antibodies promote tumor progression by inducing accumulation of myeloid-derived suppressor cells (MDSCs) in pre-clinical cancer models. Results were published online in Cancer Immunology ...

Recommended for you

Aspirin could play valuable role as additional treatment for cancer

September 26, 2018
Regular use of aspirin could help in the treatment of some cancers, finds a new review of 71 medical studies.

Lung cancer drug could be repurposed to target 'zombie' proteins linked to leukemia

September 25, 2018
A new study by scientists at the University of Liverpool highlights how a clinically-approved lung cancer drug could potentially be 'repurposed' to design new treatments for future cancer therapies.

A protein called vaccinia-related kinase 1 may help cancer establish itself in new areas of the body during metastasis

September 25, 2018
Sometimes negative results can point researchers in the right direction.

Combo therapy of prostatectomy plus radiotherapy may improve survival in prostate cancer

September 25, 2018
High-risk prostate cancer, that which has continued to grow but not yet metastasized, is commonly treated with combination therapies. Each method has pros and cons, but there is little clarity whether one might be more effective ...

Brigatinib becomes potential new first-line option for ALK-positive non-small lung cancer

September 25, 2018
Results of a 275-patient, multi-national phase III clinical trial known as ALTA-1L published today in the New England Journal of Medicine and presented concurrently in the press program at the International Association for ...

Two studies describe improved approach to bone marrow transplant

September 25, 2018
Two recent studies in the journal Leukemia present a new approach for bone marrow donation and transplant that preclinical laboratory tests suggest could make the life-saving procedure safer and more effective for patients.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.