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Keyword: cancer immunotherapy

Co-administering a monoclonal antibody that neutralizes tumor-released soluble MHC I chain-related molecule (sMIC) improves anti-CTLA4 antibody therapy effectiveness and reduces treatment-related colitis, report Medical University of South Carolina (MUSC) investigators in an article published online May 17, 2017 by Science Advances.

Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) can be thought of as an 'off switch' or 'immune checkpoint' for effector T cells that are activated to fight cancer tumors. Researchers have developed a therapy to block CTLA4, specifically, anti-CTLA4 antibody immunotherapy, to help sustain T-cell activation and improve patient survival.

Unfortunately, while anti-CTLA4 therapy is highly effective in animals, response rates in humans vary widely and serious adverse events such as colitis (gastrointestinal inflammation) are common. For example, Ipilimumab, an FDA-approved anti-CTLA4 antibody therapy for advanced melanoma, is highly effective in controlling tumors in mice but has a response rate of only fifteen percent in humans. Clinical investigators have tried to improve the efficacy and safety of anti-CTLA4 therapy by combining it with other agents but response rates and toxicity remain suboptimal.

MUSC cancer immunologist Dr. Jennifer WuA team of MUSC researchers led by Jennifer Wu, Ph.D., professor of Microbiology and Immunology, suspected that response disparities between humans and animals may be due to differences in immune modulators that human tumors express.

"When we use animals to study therapies for humans we often neglect certain human-specific biological pathways simply because they don't exist in the animal," explains Wu. "MIC is one of those molecules that is expressed in human tumors but is absent in mice. We knew that the soluble form, sMIC, is highly immunosuppressive in humans and we knew it was important, but we had no way to study it. We had to create a new model."

Their work to unravel these molecular-level differences has now paid off, with the discovery of a new combination therapy that dramatically improves CTLA4 therapy effectiveness and avoids therapy-induced colitis.

The team developed a clinically relevant, MIC-transgenic spontaneous mouse tumor model that closely resembled the onco-immune dynamics seen in human cancers. Using this model, they investigated how tumor-derived, human sMIC affected anti-CTLA4 therapy. They found that high blood levels of sMIC not only reduced the antitumor efficacy of anti-CTLA4 therapy but also directly evoked colitis.

"It was a total surprise, and we were a little nervous about the results," says Wu. "So, we repeated the test using multiple models and antibodies and different batches of animals to make sure it was reproducible and that what we were seeing was real. Sometimes knowledge itself gets in the way. Because there are certain accepted beliefs that make you think what you're seeing can't be true-that it's impossible. But when multiple experiments are all coming up with the same results, what can you say? That's when we have to let go and come to a new understanding."

Next, the team co-administered an antibody called B10G5 that neutralizes sMIC, alongside anti-CTLA4 therapy. The new combination therapy not only remarkably improved anti-CTLA4 immunotherapy effectiveness, but also alleviated therapy-induced colitis.

"We've been studying B10G5 for a while and published a paper in Clinical Cancer Research in 2015 demonstrating that using B10G5 to target sMIC can alleviate tumor-induced immune suppression and also has a huge immune-stimulating ability," explains Wu. "So those results led us to think it would be a good strategy to combine B10G5 with antibodies that target immune checkpoint molecules, the 'off-switch' of an ongoing immune response."

Finally, inspired by a case study published in 2006, the team decided to try to validate its current findings in humans. The original case reported a melanoma patient who developed anti-MIC autoantibody during anti-CTLA4 therapy and had a superior therapeutic response. So, they contacted a long-time collaborator at Oregon Health and Science University and Knights Cancer Center to obtain plasma samples collected during a clinical trial they were conducting in metastatic prostate cancer patients.

Wu's team looked for anti-sMIC autoantibodies in samples from ten patients receiving anti-CTLA4 therapy with Ipilimumab. One sample showed high levels of anti-MIC autoantibody. When the team followed up with their colleague, it turned out that this particular cancer patient not only demonstrated a remarkable therapeutic response (his prostate-specific antigen fell from 191 to 4.6 ng/ml after eight treatment cycles) but also did not develop autoimmune colitis.

That case reinforced the team's preclinical in vivo findings that coadministering the sMIC-neutralizing antibody (B10G5; CanCure, LLC) enhances anti-CTLA4 therapy and deters colitis. Overall, these results indicate a new, powerful combination immunotherapy for cancer. They also suggest that pre-screening serum sMIC levels might help clinicians to identify patients who are most likely to have a positive therapeutic response.

"I hope that our findings will inspire investigators to revisit other cancer immunotherapies that were successful in animals but presented no efficacy in humans," says Wu. "Anti-CTLA4 therapy is approved for melanoma and also is still in trials for other cancers. Maybe our study will inspire clinical investigators to think about screening their patients to identify who will be a better responder versus a poor responder to anti-CTLA4 therapy."

"Juicing" Th17 cells with FDA-approved small molecule beta-catenin and p110 delta inhibitors during in vitro expansion for adoptive T cell therapy (ACT) profoundly improves their therapeutic properties, report investigators at the Medical University of South Carolina (MUSC) in an article published online ahead of print on April 20, 2017 by JCI Insight.

MUSC cancer immunologist Dr. Chrystal M. PaulosACT involves harvesting T cells, rapidly amplifying and/or modifying them in the laboratory to boost their cancer-fighting ability, and then reinfusing them back to the patient to boost anticancer immunity. One challenge for ACT has been that the rapid expansion of T cells in the laboratory can cause them to age and wear out, decreasing their longevity after reinfusion.

"Juicing" Th17 cells with the FDA-approved small molecules enhanced their potency, function and stem-like (less differentiated) quality, suggesting that they would persist better after reinfusion into patients, and also reduced regulatory T cells in the tumor microenvironment, which can blunt the immune response. These findings highlight novel investigative avenues for next-generation immunotherapies, including vaccines, checkpoint modulators, and ACT.

"This is exciting because we might be able to overcome some of the delays and disadvantages of rapid expansion in the laboratory," explains senior author Chrystal M. Paulos, Ph.D., associate professor of immunology and Endowed Peng Chair of Dermatology at MUSC and a member of the MUSC Hollings Cancer Center. "We might be able to use fewer cells (for ACT) because we can pharmaceutically 'juice' these T cells to make them more fit in the oppressive tumor microenvironment."

Building upon their previous findings that ICOS costimulation is critical for generating human Th17 cells and for enhancing their antitumor activity, an MUSC research team led by Paulos and including postdoctoral fellow Kinga Majchrzak report for the first time that repurposing FDA-approved small molecule drugs that inhibit two ICOS-induced pathways greatly enhances the antitumor potency of T cells.

Several biologic properties of the Wnt/ beta-catenin and P13K delta pathways led the team to suspect that they supported the antitumor activities of Th17 cells. For example, these pathways are active in both regulating T cell cytokine production during the immune response and in promoting self-renewal of hematopoietic stem cells (HSCs) and sustaining HSCs in an undifferentiated state. So, they designed a series of experiments to determine whether these two pathways were also active in enhancing Th17 antitumor memory and effectiveness.

To test this idea, they pharmaceutically inhibited PI3K delta and beta-catenin in Th17 cells (using idelalisib [CAL-101] to block the PI3K delta pathway and indomethacin [Indo] to inhibit beta-catenin)-anticipating that this would weaken Th17 cells' antitumor activity. To their surprise, the exact opposite occurred. ICOS-stimulated Th17 cells that were treated in vitro with CAL-101 plus Indo elicited a more potent antitumor response against melanoma in mice.

"My post-doc student came to me and said, 'I think I made a mistake because the data are going in the opposite direction to what we originally predicted!" says Paulos. "So, she repeated the experiment several times but we kept getting the same result. The data showed that using drugs to inhibit these pathways actually made the Th17 cells even better at killing tumors."

The team found that Th17 cells treated with CAL-101 express less FoxP3, suggesting that the drug suppresses Treg conversion while sustaining central memory-like Th17 cells. This finding is highly important because the phenotypic plasticity of Th17 cells in vivo allows their conversion to Tregs or Th1 cells with weak antitumor properties. These data suggest that treatment with CAL-101 can halt the development of these poorly therapeutic phenotypes and, thus, enhance the T cells' antitumor activity.

While the findings were initially counterintuitive and perplexing from a mechanistic perspective, in retrospect Paulos sees that they make sense. "Essentially, the T cells are younger," explains Paulos. "We know that T cells used for ACT age and wear out over time. Somehow these drugs sustain their youth and function. They're able to keep all the properties of their youth-they expand better and they're more functional and handle the oppressive tumor microenvironment better."

The discovery that existing FDA-approved drugs that block p110 delta and beta-catenin can make T cells more efficient tumor killers in vivo is an exciting prospect for Paulos' team. "From a clinical standpoint, this finding indicates that the therapeutic effectiveness of ACT could be improved by simple treatments with readily available drugs. It opens a lot of new investigative avenues for next-generation immunotherapy trials," she says.

"This research offers tremendous promise for the treatment of patients with serious forms of skin cancer," says Dirk M. Elston, M.D., chair of the Department of Dermatology and Dermatologic Surgery at MUSC.

Paulos has a patent on ICOS signaling in adoptive T cell transfer therapy (US 9133436), and Paulos, Majchrzak, and J.S. Bowers have a patent on pharmaceutical drug combinations or genetic strategies that instill durable antitumor T cell memory and activity (patent application P1685).

T cell attacking a tumor

T cell attacking a tumor

 

 

Stylized image of a T cell attacking a tumor. Illustration by Emma Vought.


 

 

 

 

 

 

 

 

 

 

 

 

Release Summary: The protein moesin could be a target for cancer immunotherapy, report Medical University of South Carolina (MUSC) investigators in an article in the Journal of Clinical Investigation. Their data suggest that moesin promotes conversion of naive T cells into regulatory T cells that suppress the immune response against cancer. Inhibiting moesin could help restore the anti-tumor T cell response and also improve the survival of cancer-killing CD8+ cells after adoptive T cell transfer.

In an article published online ahead of print on March 13, 2017 by the Journal of Clinical Investigation, Medical University of South Carolina (MUSC) investigators report preclinical research showing that moesin, a membrane-domain organizing protein, controls regulatory T cell (Treg) function as well as the abundance and stability of transforming growth factor-beta (TGF-beta) receptors on the surface of cells, providing a potential therapeutic target for cancer immunotherapy.

Their findings show that TGF-beta acts at the protein level to generate Tregs in the tumor microenvironment. Although the human immune system is capable of eradicating cancer, Tregs dampen the immune response and protect cancer cells against tumor-killing (i.e., cytotoxic) T cells. The MUSC study is the first to show that eliminating moesin reduces TGF-beta receptor expression and subsequent Treg generation to restore anti-tumor immunity.

T cells, a subtype of white blood cells, can effectively attack and kill tumor cells when activated by the protein TGF-beta. However, the immune system has a sophisticated network of checks and balances to ensure that the body does not produce so many of these cytotoxic T cells that it harms its own cells and tissues. When the immune reaction is complete, TGF-beta signals naive T cells to become Tregs that suppress and degrade the activated, inflammatory T cells, ensuring that they do not overproduce the immune factors that can lead to autoimmune disease.

Cancer cells have learned to hijack this system of checks and balances to hide from the tumor-killing T cells. Many cancers produce TGF-beta that binds the receptors on the tumor-killing helper T cells so they can’t be recruited to fight the tumor. The T cells convert instead to Tregs, which suppress the immune response against the cancer.

Inhibiting moesin could help prevent conversion of naive T cells into Tregs, thereby restoring the anti-tumor immune response. 

"Because moesin supports greater Treg production, we could design moesin inhibitors to halt or slow active TGF-beta signaling and slow down Treg conversion so that anti-tumor T cells can have a chance to see the cancer and eradicate it,” explains Zihai Li, M.D., Ph.D., chair of the Department of Microbiology and Immunology at MUSC and senior author on the paper.

Earlier studies by Philip Howe, Ph.D., chair of MUSC's Department of Biochemistry and Molecular Biology and a co-author on the paper, demonstrated that many TGF-beta-mediated epithelial mesenchymal transition genes, including moesin, were repressed by an RNA-binding protein in healthy epithelial cells and that moesin expression could be restored through TGF-beta stimulation.

This ability of TGF-beta to dramatically increase moesin expression led the team to investigate moesin’s role in Treg generation. Jointly with other colleagues at MUSC, the team compared the abilities of helper T cells with and without moesin to become Tregs. They found that moesin promotes Treg generation by interacting with a TGF-beta receptor to make it more available, thereby enhancing TGF-beta signaling. Conversely, TGF-beta signaling was reduced in the absence of moesin, impairing the development and function of Tregs.

Perhaps the most compelling results were provided by studies involving adoptive T cell therapy in a mouse model of melanoma. In adoptive T cell therapy, tumor-killing T cells are “harvested” from a human or animal with cancer and amplified or otherwise “supercharged” before being reinfused into the donor. Although these reinfused cells can be very effective at killing tumors, they do not always survive long-term, setting the stage for recurrence. 

The MUSC research team showed that these reinfused anti-cancer CD8+ T cells not only underwent rapid activation and expansion in mice lacking moesin, but that they also survived longer, reducing the likelihood of recurrence. Indeed, after adoptive T cell transfer, all of the mice having moesin relapsed while most of the mice lacking moesin were cured.

"When the mice lacking moesin had no recurrence, this was really exciting. We were not only deleting moesin but, when we gave T cells to the active tumors, those T cells could control the cancer for a very long time,” explains Ephraim Ansa-Addo, Ph.D., a postdoctoral fellow in the Department of Microbiology and Immunology and lead author on the paper.

These findings suggest that moesin could be a therapeutic target in developing new treatments for cancer and Treg-related immune disorders. Chemical modulators of moesin could control the function of T cells by inhibiting moesin in cancers or inducing it to treat autoimmune diseases. Moesin modulators could also be combined with current immunotherapy regimens.

“These findings are very interesting for the field and provide a lot of directions for further research into alternative therapies," says Li.

It is now accepted that our immune system is capable of mounting an attack against cancer. However, tumors have devised ways to elude detection and to render tumor reactive or “effector” T cells indolent. Cancer immunotherapies such as adoptive T cell transfer (ACT) seek to reinvigorate and reinforce tumor-reactive cells so that they can effectively target tumor.

In ACT therapy, exhausted T cells in the vicinity of a tumor are harvested; expanded, conditioned, and sometimes genetically reengineered to better recognize and target the tumor; and then reinfused. T cell growth factors, such as interleukin (IL) 2 and IL-15, are often administered to promote proliferation of the reinfused T cells that have been trained to target the patient’s tumor. IL-15 is a more recently discovered cytokine and seems to promise some advantages over IL-2, which is toxic at therapeutic doses and which can stimulate regulatory T cells that blunt the effect of effector T cells.  One limitation of translating this therapy to the clinic is that preconditioning with chemotherapy or radiation is required for best results. Chemotherapy and radiation are expensive, associated with substantial adverse effects, and require hospital admission.T cells expressing IL-2 receptor alpha outcompete host cells for IL-2

In an article published in the October 28, 2015 issue of Science Translational Medicine, senior author Mark P. Rubinstein, Ph.D., and his colleagues in the Department of Surgery and the Department of Microbiology and Immunology at the Medical University of South Carolina and his collaborators at the University of California San Diego report the surprising finding that curative responses were achieved with ACT in a mouse model of melanoma without lymphodepletion when IL-2 but not IL-15 was co-administered. These findings are important because they suggest that low-dose IL-2 could be used as an alternative to chemotherapy and radiation as a preconditioning regimen for ACT therapy.

Host cells are thought to outcompete the reinfused or “donor” cells for T cell growth factors such as IL-2 and IL-15. Chemotherapy and radiation knock down the number of host cells so that the donor cells can more effectively compete for IL-2 or IL-15.  Rubinstein and his colleagues found that curative responses were achieved with IL-2 without lymphodepletion when the effector T cells were engineered to express elevated levels of IL-2 receptor alpha (IL-2R?). The presence of IL-2R? on the surface of the effector T cells enabled them to outcompete host cells for IL-2. This suggests that, if the effector T cells harvested from patients are engineered to express high levels of IL-2R?, then low doses of IL-2 may be adequate to achieve significant clinical response, making preconditioning with chemotherapy or radiation unnecessary.

The study authors also describe a novel mechanism that helps account for the ability of IL-2 to mediate curative responses in the absence of chemotherapy or radiation. They found that, in T cells expressing IL-2R?, IL-2 does not degrade as expected after being taken up by the effector T cell. Instead, IL-2R? rescues IL-2 from being degraded, thereby enabling IL-2 to be recycled so it can continue to optimize effector T cell response. “The ability of IL-2R? to sustain IL-2 signaling provides a molecular mechanism to explain how IL-2 therapy may be particularly useful clinically,” says Rubinstein. “This mechanism could provide a novel way to enhance the tumor-killing potential of T cells transferred to patients in the absence of prior chemotherapy or radiation.”

 The lead researchers in the Rubinstein laboratory for this study were Ee Wern Su, Ph.D.,and Caitiln Moore. Ms. Moore is currently in medical school at MUSC. For a complete list of authors, please view the article's abstract.

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