Tag Archives: #immunotherapy

Researchers Uncover a Way to Harness the Power of Immunotherapy for Advanced Prostate Cancer (Medicine)

It’s a scientific riddle tangled up in a complex web. How do you turn an immune cold cancer into one that responds to immunotherapy?

Researchers led by the University of Michigan Rogel Cancer Center started with a simple thread: an inhibitor that showed promise against metastatic castration-resistant prostate cancer cells. This is the most challenging type of prostate cancer – advanced disease that has become resistant to hormone-based treatment.

From there, they continued to untangle the web to discover multiple levels of cellular processes that were preventing the immune system from mounting a response. Break past them with this inhibitor and suddenly what’s considered an immune cold tumor turns red hot.

Immunotherapy has dramatically improved outcomes for some types of cancer. But prostate cancers are typically immune cold, which means these patients have benefited little from immunotherapies. Finding a way to rev up the immune response would create tremendous opportunity to improve patient outcomes,” says Arul M. Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology and S.P. Hicks Professor of Pathology at Michigan Medicine. Chinnaiyan is senior author of the paper published in Nature Cancer.

Researchers started by screening a library of 167 inhibitors against prostate cancer cells. They found one, ESK981, had the most impact.

ESK981 is a class of drugs called multi-tyrosine kinase inhibitors, which are designed to hit multiple targets. This means it functions like a combination therapy, able to block cancer on more than one front. It was originally developed to check blood vessel growth and has already been tested in phase 1 clinical trials, which found it to be safe and well-tolerated.

In cell lines and mice with metastatic castration-resistant prostate cancer, researchers found ESK981 inhibited tumor growth.

“The response was intriguing, but we wanted to understand the mechanism at play with ESK981 in prostate cancer cells,” Chinnaiyan says.

They discovered several cellular processes were occurring. First was the role of a type of cell death called autophagy. The authors surprisingly found that ESK981 was a potent inhibitor of autophagy in tumor cells. This caused the cancer cells to produce a protein called CXCL10, which led to recruitment of immune T cells to the tumor.

But there was one more layer to go. Ultimately, they traced it back to PIKfyve, a type of protein called a lipid kinase. The authors discovered that ESK981 directly targets PIKfyve, affecting these multiple processes involved in metabolism and cell death.

The researchers confirmed this by knocking down PIKfyve in cell lines and mice. They saw the same processes occur: tumors stopped growing, autophagy was controlled and more T cells were recruited to the tumor. When they added an immune checkpoint inhibitor to the PIKfyve knockdown, the impact was even greater, significantly reducing tumors.

“Overcoming resistance to immunotherapy is an urgent need in prostate cancer. PIKfyve is a promising target, especially combined with an immune checkpoint inhibitor. This combination has potential to extend the benefit of immunotherapy to patients whose tumors have previously not responded,” Chinnaiyan says.

Based on these findings, researchers have begun phase 2 clinical trials using ESK981 alone or in combination with the immunotherapy nivolumab for metastatic castration-resistant prostate cancer.

Additional authors: Yuanyuan Qiao, Jae Eun Choi, Jean C. Tien, Stephanie A. Simko, Thekkelnaycke Rajendiran, Josh N. Vo, Andrew D. Delekta, Lisha Wang, Lanbo Xiao, Nathan B. Hodge, Parth Desai, Sergio Mendoza, Kristin Juckette, Alice Xu, Tanu Soni, Fengyun Su, Rui Wang, Xuhong Cao, Jiali Yu, Ilona Kryczek, Xiao-Ming Wang, Xiaoju Wang, Javed Siddiqui, Zhen Wang, Amelie Bernard, Ester Fernandez-Salas, Nora M. Navone, Stephanie J. Ellison, Ke Ding, Eeva-Liisa Eskelinen, Elisabeth I. Heath, Daniel J. Klionsky, Weiping Zou

Funding: Prostate Cancer Foundation Challenge Award, National Cancer Institute Prostate SPORE Grant P50CA186786, Department of Defense grant PC130151P1, National Institutes of Health grant GM131919.

In addition, individual researchers are supported by NCI grant R35CA231996, Howard Hughes Medical Institute, A. Alfred Taubman Institute, American Cancer Society, PCF Young Investigator Awards, DoD Postdoctoral Award W81XWH-16-1-0195, and the Academy of Finland.

Disclosure: The University of Michigan has filed a disclosure on the findings based on this study. Chinnaiyan and Qiao are named as co-inventors. Esanik Therapeutics Inc. licensed ESK981 from Teva Pharmaceuticals. Chinnaiyan is a co-founder and serves on the scientific advisory board of Esanik Therapeutics Inc. Esanik Therapeutics or Teva Pharmaceuticals were not involved in the design or approval of this study, nor was this study funded by them.

Featured image: Researchers in the Chinnaiyan Lab © Credit: University of Michigan Rogel Cancer Center


Paper cited: “Autophagy inhibition by targeting PIKfyve potentiates response to immune checkpoint blockade in prostate cancer,” Nature Cancer. DOI: 10.1038/s43018-021-00237-1


Provided by University of Michigan

Study Identifies Biomarker For Breast Cancer Response To Immunotherapy (Medicine)

A biomarker that has proven to be a predictor for response to immunotherapies in melanoma patients also has clinical relevance for breast cancer patients, according to a new study published in Clinical Cancer Research.

The study demonstrated that this biomarker, a molecule called the Major Histocompatibility Complex Class II protein (MHC-II), has the potential to be a predictor of immunotherapy benefit with two types of breast cancer—early-stage, triple negative breast cancer (TNBC) and high-risk, estrogen receptor-positive breast cancer (HR+) when expressed on breast cancer cells. Although immunotherapies are likely to soon be prescribed along with chemotherapies for these breast cancers before surgery, most patients don’t require the addition of immunotherapy to achieve treatment response. Without an optimal biomarker, clinicians don’t have a reliable way to discern which patients need immunotherapy and which ones don’t.

Clinical tests for MHC-II expression could shield breast cancer patients who don’t need the immunotherapy from possible treatment complications and additional costs. Immunotherapies are expensive and associated with significant toxicity.

Justin Balko, PharmD, Ph.D., associate professor of Medicine and Pathology, Microbiology and Immunology, conceived and designed the study.

“These findings are particularly exciting for us, because if validated, they could provide a better way to personalize therapy for breast cancer patients. So far, the typical biomarkers like PD-L1 expression and the numbers of immune cells in the tumor have not done a good job of identifying patients who need immunotherapy,” said Balko, the study’s senior author.

Paula Gonzalez Ericsson, the study lead author, added, “the test can be easily performed on patient’s tissue samples obtained for diagnosis without the need of additional intervention.”

Balko and colleagues analyzed tissue samples donated by three cohorts of patients:

  • patients with non-immunotherapy-treated breast cancers
  • patients with TNBC treated with the immunotherapy durvalumab and standard chemotherapy
  • patients with HER2-negative breast cancer treated with either standard chemotherapy or the standard chemotherapy plus the immunotherapy pembrolizumab.

They determined that MHC-II is expressed in a subgroup of primary TNBC and HR+ breast cancers, and that tumor MHC-II expression is associated with response to standard chemotherapy plus durvalumab or pembrolizumab, but not to standard neoadjuvant chemotherapy alone.

“The findings of the association with response in early-stage high-risk HR+ patients suggests that MHC-II may be a useful tool in a broader context for breast cancer and this area would benefit from further study,” said co-senior author, Kim Blenman, Ph.D., MS, assistant professor of Medicine at Yale University.

The study is believed to be the first to evaluate and demonstrate the predictive capacity of tumor MHC-II for immunotherapy-specific benefit in patients with breast cancer. The researchers also noted that MHC-II has the potential to be a pan-cancer biomarker predictor for anti-PD-1 or anti-PD-L1 immunotherapies since its clinical relevance has been demonstrated with melanoma, breast cancer and Hodgkin’s lymphoma in this study and previous studies. However, they call for a large, randomized controlled trial to validate their findings with breast cancer, which was based on a retrospective tissue-based analysis.


Reference: Paula I Gonzalez-Ericsson et al, Tumor-specific major histocompatibility-II expression predicts benefit to anti-PD-1/L1 therapy in patients with HER2-negative primary breast cancer, Clinical Cancer Research (2021). DOI: 10.1158/1078-0432.CCR-21-0607


Provided by Vanderbilt University Medical Center

Cancer: Immunotherapies Without Side Effects? (Medicine)

By identifying the mechanism of toxicity induced by immunotherapies, scientists from UNIGE and from the Harvard Medical School are paving the way for cancer treatments with fewer side effects.

In recent years, immunotherapy has revolutionised the field of cancer treatment. However, inflammatory reactions in healthy tissues frequently trigger side effects that can be serious and lead to the permanent discontinuation of treatment. This toxicity is still poorly understood and is a major obstacle to the use of immunotherapy. Scientists from the University of Geneva (UNIGE), Switzerland, and Harvard Medical School, United States, have succeeded in establishing the differences between deleterious immune reactions and those targeting tumour cells that are sought after. It appears that while the immune mechanisms are similar, the cell populations involved are different. This work, published in the journal Science Immunology, makes it possible to envisage better targeted, more effective, and less dangerous treatments for cancer patients.

Based on massive stimulation of the patient’s immune system, immunotherapies have saved many lives. Unfortunately, they are not without consequences. “When the immune system is activated so intensively, the resulting inflammatory reaction can have harmful effects and sometimes cause significant damage to healthy tissue”, says Mikaël Pittet, holder of  the ISREC Foundation Chair in Onco-Immunology at UNIGE Faculty of Medicine Department of Pathology and Immunology and Centre for Translational Research in Onco-Haematology, and a member of the Swiss Cancer Centre Leman. “Therefore, we wanted to know if there are differences between a desired immune response, which aims to eliminate cancer, and an unwanted response, which can affect healthy tissue. The identification of distinctive elements between these two immune reactions would indeed allow the development of new, more effective and less toxic therapeutic approaches.”

Using liver biopsy samples from patients treated at the CHUV and the HUG who had suffered such toxic reactions, the scientists studied the cellular and molecular mechanisms at work to reveal similarities and dissimilarities.


A similar response, but with different cells

In an immunotherapy-related toxic response, two types of immune cells — macrophage and neutrophil populations — appear to be responsible for attacking healthy tissue, but are not involved in killing cancer cells. In contrast, another cell type — a population of dendritic cells — is not involved in attacking healthy tissue but is essential for eliminating cancer cells. “Immunotherapies can trigger the production of specialised proteins that alert the immune system and trigger an inflammatory response, explains Mikaël Pittet. In a tumour, these proteins are welcome because they allow the immune system to destroy cancerous cells. In healthy tissue, however, the presence of these same proteins can lead to the destruction of healthy cells. The fact that these inflammatory proteins are produced by such different cells in tumours and healthy tissue is therefore an interesting finding.”

Dendritic cells are very rare, whereas macrophages and neutrophils are much more common. Some macrophages are present in most of our organs from embryonic development stages and remain there throughout our lives. Contrary to what was previously thought, these macrophages do not necessarily inhibit inflammation but, stimulated by immunotherapies, can trigger a harmful inflammatory response in the healthy tissue where they reside, thus explaining why toxicity can affect different organs.


Neutralising neutrophils for a double benefit

When macrophages are activated by drugs, they produce inflammatory proteins. These in turn activate neutrophils, which execute the toxic reaction. “This opens the possibility of limiting immunotherapy’s side effects by manipulating neutrophils”, says Mikaël Pittet.

The research team confirmed their discovery by studying the immune reactions of mice whose cell activity was modulated with genetic tools. They were able to identify a loophole that could be exploited to eliminate these side effects. Indeed, neutrophils produce some factors that are important for the development of toxicity, including TNF-α, which could be a therapeutic target. TNF-α inhibitors are already used to modulate the immune response in people with arthritis and could perhaps be useful in the cancer setting to inhibit the toxic effects of neutrophils during immunotherapy. “Furthermore, inhibiting neutrophils could be a more effective way to fight cancer: in addition to triggering a toxic response, some of these cells also promote tumour growth. Thus, by managing to control them, we could have a double beneficial effect: overcome the toxicity in healthy tissues, and limit the growth of cancerous cells”, concludes Mikaël Pittet.

The Swiss Cancer Centre Léman is a network that brings together the universities of Geneva (UNIGE) and Lausanne (UNIL), the EPFL, the HUG and the CHUV under the same banner. This alliance brings together, under a federating and regional identity, all the specialists in the chain leading from the laboratory to the bedside.

This research is published in
Science Immunology
DOI: 10.1126/sciimmunol.abi7083

Featured image: In yellow: liver macrophages, or Kupffer cells, which secrete the IL-12 protein that causes adverse effects of immunotherapy. In blue, blood vessels. © UNIGE – Mikaël Pittet


Provided by University of Geneve

Cell-based Immunotherapy Shows Promise Against Melanoma (Medicine)

Effective against blood cancers, natural killer cells also may be effective against solid tumors

An immunotherapy based on supercharging the immune system’s natural killer cells has been effective in treating patients with recurrent leukemia and other difficult to treat blood cancers. Now, researchers at Washington University School of Medicine in St. Louis have shown in preclinical studies conducted in mice and human cells that this type of cell-based immunotherapy also could be effective against solid tumors, starting with melanoma, a type of skin cancer that can be deadly if not caught early.

The study is published June 29 in Clinical Cancer Research, a journal of the American Association for Cancer Research.

In recent years, an immunotherapy called immune checkpoint inhibitors has revolutionized treatment for advanced melanoma. In one well-known example, this immunotherapy was successfully used to treat former President Jimmy Carter, whose melanoma had spread to his liver and brain.

But the therapy only works in about half of such patients. And even among those who respond well to the initial therapy, about half go on to develop resistance to it. Consequently, researchers have been seeking different ways to harness the immune system to attack melanoma cells. One possibility is to use natural killer (NK) cells, a part of the immune system’s first line of defense against dangerous cells, whether cancer cells or invading bacteria.

Todd A. Fehniger, MD, PhD, a professor of medicine, and his team have had success in clinical trials treating recurrent leukemia with a patient’s own natural killer cells or those from a donor. The NK cells are harvested from the patient’s or a donor’s blood and exposed to a set of chemical signals called cytokines that activate the cells and prime them to remember this activation. When these “cytokine-induced memory-like” NK cells are given to the patient, they are more potent in attacking the cancer because they already have been revved up, as Fehniger puts it.

“These ‘revved-up’ memory-like NK cells attack blood cancers quite well,” said Fehniger, the study’s co-senior author and an oncologist who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “But relatively little work has been done on whether these cells can be used against solid tumors. This is an unmet need in solid tumor oncology. Our study provides proof of principle that memory-like NK cells respond better than normal NK cells against melanoma, and it serves as a stepping stone to a first-in-human clinical trial of these cells in advanced melanoma.”

Added co-senior author Ryan C. Fields, MD, the Kim and Tim Eberlein Distinguished Professor of Surgical Oncology: “We hope this is also a step toward harnessing NK cells against multiple solid tumors. Melanoma was a good place to start because we know it responds to immune therapy. But because many patients don’t respond or develop resistance, we felt that targeting a different aspect of the immune system was a promising strategy to pursue.”

The standard checkpoint inhibitor immunotherapy that works well in some melanoma patients targets T cells, another type of immune cell that also frequently is harnessed against different forms of cancer. According to the researchers, patients who don’t respond well or stop responding to the T cell-based standard therapy and have no other options would be good candidates for NK cell therapy.

The researchers studied human NK cells from both healthy people and from patients with melanoma and found that the cytokine-induced memory-like NK cells could effectively treat mice harboring human melanoma tumors. Tumors shrank to the point of being almost undetectable in many of the mice, and the memory-like NK cells prevented the tumors from returning in most cases for the duration of the 21-day experiment. While normal NK cells also reduced and controlled melanoma tumors, they did not do so to the same degree.

“We are currently designing a clinical trial to evaluate these NK cells in patients with advanced melanoma who have exhausted all other treatment options,” Fehniger said. “We would like to investigate NK cells from a donor and, separately, a patient’s own NK cells to see if the cytokine-induced memory-like NK cells offer an effective treatment option for patients with this aggressive skin cancer.”

The NK cell-based immunotherapy is potentially safer than other cell-based immunotherapies because the NK cells do not trigger a cytokine storm, as is seen sometimes in CAR-T cell therapy, which often is used for blood cancers, nor do the NK cells cause graft-versus-host disease, which sometimes follows a stem cell transplant.

“Even 10 years ago, we had no effective therapies for advanced melanoma — much like the lack of therapies for glioblastoma or advanced pancreatic cancer today,” said Fields, a surgeon who treats patients at Siteman. “Checkpoint immunotherapy has revolutionized melanoma treatment, but we’re still not satisfied with the 50% response rate. We want to do better, and this NK cell therapy is a promising approach. And in the future, we may be able to combine an NK cell-based therapy with checkpoint inhibition for an even better response.”

Fehniger and his colleagues have worked with Washington University’s Office of Technology Management to license the cytokine-induced memory-like NK cell technology to a company called Wugen. Fehniger is a co-founder of Wugen and serves on its scientific advisory board.

Fehniger and co-author Melissa M. Berrien-Elliott, PhD, an instructor in medicine, are consultants and have equity interest in Wugen and may receive royalty income based on technology they developed and that was licensed by Washington University to Wugen.

This work was supported by the National Institutes of Health, grant numbers T32 HL007088; R01CA248277, R01CA205239, CCSG P30 CA091842, NIHU54CA224083, K12CA167540, and a SPORE in Leukemia P50CA171063. Additional funding was provided by a Sidney Kimmel Translational Science Scholar Award; a Society of Surgical Oncology Clinical Investigator Award; the David Riebel Cancer Research Fund; the Leukemia and Lymphoma Society; the V Foundation for Cancer Research; and the AAI Intersect Fellowship Program for Computational Scientists and Immunologists. Research reported in this publication was supported by the Washington University School of Medicine Surgical Oncology Basic Science and Translational Research Training Program, grant number T32CA009621 from the National Cancer Institute. Further support was provided by the Siteman Flow Cytometry Core; the Immune Monitoring Lab; the Siteman Tissue Procurement Core; and the core grant/services of the Washington University Digestive Diseases Research Core Center, grant number P30 DK052574.

Featured image: A new study from Washington University School of Medicine in St. Louis demonstrates, in mice and human cells, that a cell-based immunotherapy may be effective against melanoma. Until now, such therapy — based on the immune system’s natural killer cells — has only been used against blood cancers. Shown are three “memory-like” natural killer cells (red) attacking a melanoma cancer cell (green). The white areas show toxic molecules that the natural killer cells use to destroy the tumor cell. © NANCY MARIN/FEHNIGER LAB


Reference: Marin ND, et al. Memory-like differentiation enhances NK cell responses to melanoma. Clinical Cancer Research. June 29, 2021.


Provided by Washington University School of Medicine in St Louis

Anti-cancer Immunotherapy Drug With Reduced Side Effects and Increased Therapeutic Effects (Medicine)

Development of anti-cancer drugs that boost patient immunity. Potential for immunotherapy drug with no side effects

Unlike conventional cancer drugs that attack and kill cancer cells directly, anti-cancer immunotherapy, which kills cancer cells by strengthening the body’s immunity, is a novel type of cancer treatment currently attracting increased attention. Unfortunately, a minority of cancer patients who have some degree of pre-existing immunity only benefit from anti-cancer immunotherapy.

Recently, ‘doxorubicin’, a cancer treatment drug, has been shown to boost patients’ immune response by releasing various components when cancer cells are killed. However, as the toxicity and inflammatory responses induced by doxorubicin can affect normal cells in addition to cancer cells, it can lower patients’ immunity levels, which limits its effectiveness for immunotherapy.

To tackle this issue, a research team led by Dr. Ju Hee Ryu of the Center for Theragnosis at the Korea Institute of Science and Technology (KIST) has developed an anti-cancer prodrug that can improve anti-cancer immunotherapy by reacting only with cancer cells, thereby minimizing the toxicity to normal cells, including immune cells, and boosting patient immunity.

Last year, the Center for Theragnosis at KIST reported the development of an anti-cancer drug that targets cancer cells by suppressing the resistance to doxorubicin without reacting with normal cells. In contrast, Dr. Ryu’s research team has developed a prodrug for anti-cancer immunotherapy that utilizes the immunity-boosting potential of doxorubicin.

The developed prodrug exhibits anticancer effects when activated by abundant enzymes present in cancer cells. As these enzymes are not present in normal cells, they do not experience toxicity and inflammatory responses. The ability to target cancer cells exclusively increases patient immunity, inducing an active anticancer immune response when doxorubicin is activated in cancer cells.

The developed anti-cancer drug significantly improved the anti-cancer immune response in nonclinical animal models and reduced side effects associated with inflammatory responses and toxicity in normal tissues. Therefore, the drug dosage can probably be increased to enhance its effectiveness for chemotherapy without causing notable side effects.

In addition, because the prodrug was developed by utilizing a drug already in clinical use, the commercialization process is expected to be relatively straightforward in terms of clinical trials and mass production.

Dr. Ju Hee Ryu of KIST said, “Because the immunity level of most patients must be raised to a certain level to enjoy the remarkable therapeutic effect of immunotherapy, an anti-cancer prodrug that can maintain the anti-cancer immune response of the drug while reducing the toxicity and inflammatory responses in normal tissues represents a significant step forward for immunotherapy.”

This study was conducted as a mid-career researcher program of the National Research Foundation of Korea with the support of the Ministry of Science and ICT (MSIT). The research results are published in the latest issue of ‘Biomaterials‘ (IF:10.317, top 2.6% in the field of JCR), a leading international journal in the field of materials and biomaterials.

Featured image: Schematic illustration of preferential immune responses during the cancer-activated DOX prodrug nanoparticle (CAP-NPs)-based chemotherapy: CAP-NPs exhibit selective tumor accumulation via enhanced permeability and retention (EPR) effect and cancer cell-specific activation by overexpressed cancer-associated cathepsin B. Consequently, CAP-NPs selectively initiate enhanced immunogenic cell death (ICD) in cancer cells by inducing cell surface exposure of calreticulin and extracellular secretion of DAMPs, as well as DC maturation and cytotoxic T cell activation in targeted tumor tissues. Concurrently, CAP-NPs significantly reduce the systemic toxicity and inflammatory response in normal organs. Furthermore, cytotoxicity to immune cells is minimized, leading to increase DCs maturation and T cell activation. © Korea Institute of Science and Technology(KIST)


Reference: Suah Yang, Man Kyu Shim, Woo Jun Kim, Jiwoong Choi, Gi-Hoon Nam, Jeongrae Kim, Jinseong Kim, Yujeong Moon, Han Young Kim, Jooho Park, Yoon Park, In-San Kim, Ju Hee Ryu, Kwangmeyung Kim, Cancer-activated doxorubicin prodrug nanoparticles induce preferential immune response with minimal doxorubicin-related toxicity, Biomaterials, Volume 272, 2021, 120791, ISSN 0142-9612, https://doi.org/10.1016/j.biomaterials.2021.120791. (https://www.sciencedirect.com/science/article/pii/S0142961221001472)


Provided by NST

UCI-led Study Finds That Cancer Immunotherapy May Self-limit its Efficacy (Medicine)

Common tumor inhibitor drug triggers favorable and unfavorable immune effects

Cancer immunotherapy involving drugs that inhibit CTLA-4 also activates an unwanted response that may self-limit its efficacy in fighting tumors, according to a new study led by Francesco Marangoni, Ph.D., assistant professor of physiology & biophysics and member of the Institute for Immunology at the University of California, Irvine. Study results are published online in the journal Cell.

Using a person’s own immune system – immunotherapy – to treat cancer may also stimulate T regulatory cells, which are essential for preventing autoimmunity, in which the body attacks healthy cells and tissue, but limit tumor control. Some anticancer drugs of the checkpoint inhibitor family block the molecule CTLA-4 and activate both the CD8 and CD4 effector T cells, which kill cancer. Using intravital microscopy, a technique that allows imaging of cells within a living organism, researchers found that CTLA-4 blockage also causes the expansion of T regulatory cells, decreasing the effect of immunotherapy.

“Much of our knowledge of the mechanisms by which immunotherapy works is focused on the positive aspects of the body’s reaction, but that treatment targets the whole immune system. In this study, we investigated how Treg cells are activated within the tumor mass. We discovered that Treg cells are continuously activated in cancer. In turn, they use CTLA-4 to instruct dendritic cells to become inefficient activators of the immune system. Upon CTLA-4 inhibition, dendritic cells become more active and promote the function of effector and regulatory T cells at the same time. This has the potential of limiting efficacy and may explain the failure of immunotherapy in some patients,” said Marangoni, corresponding author on the study.

Future research will focus on identifying and removing unwanted immune reactions in other forms of immunotherapy. In particular, new strategies must be developed to decrease the activation of Treg cells in a controlled manner in order to avoid “fatal autoimmunity,” Marangoni said: “The indiscriminate depletion of Treg cells would cause the CD8 and CD4 effector T cells to attack our body and potentially kill us.”

The research team also included physicians and scholars from Harvard Medical School and Massachusetts General Hospital in Boston, The University of Texas MD Anderson Cancer Center in Houston, and Germany’s University of Cologne and University of Lübeck. This work was supported by several National Institutes of Health grants, a Melanoma Research Foundation award and a Sara Elizabeth O’Brien/Charles A. King Trust fellowship.

Featured image: T regulatory cells (green with red nuclei) interact with antigen-presenting cells (magenta) in a tumor (blue). The Treg cell on top is activated (green fluorescence in the nucleus), while the one at the bottom is not (green fluorescence outside the nucleus). Activation of Treg cells promotes tumor growth. Courtesy of Francesco Marangoni


Provided by University of California, Irvine

‘Suffocating’ Cancer: A New Headway in Melanoma Immunotherapy (Medicine)

Disrupting cancer cell ability to adapt to low oxygen conditions shows promise in melanoma 

Hypoxia, or the inadequate oxygenation of a tissue, is a condition occurring frequently in all solid tumours such as melanoma skin cancer. Melanoma cells are not only able to survive oxygen deprivation, but also to use it to their own advantage by hijacking the anti-tumour immune response and developing resistance mechanisms to conventional anti-cancer therapies. A key gene responsible for cancer cell adaptation to hypoxia is HIF-1α (Hypoxia Inducible Factor-1 alpha). Led by Dr Bassam Janji, head of the Tumor Immunotherapy and Microenvironment (TIME) research group at the Luxembourg Institute of Health (LIH) and in collaboration with Gustave Roussy Cancer Center in France and the Thumbay Research Institute of Precision Medicine at Gulf Medical University in the United Arab Emirates, the team used gene editing technologies to show how targeting HIF-1α could not only inhibit tumour growth, but also drive cytotoxic (toxic to cells) immune cells to the cancer tissue. This discovery provided a valuable new target to make resistant melanomas more vulnerable to available anti-cancer treatments. Their findings were recently published in the reputable ‘Oncogene Journal’.

Melanoma is a type of skin cancer that develops from melanocytes, cells that are responsible for the production of pigments. Melanomas become harder to treat if not detected early, with emerging treatment resistance being an important barrier to their effective management. Due to their rapid growth rate and low blood supply, solid tumours including melanoma often exhibit areas of hypoxia. Hypoxia, or the decrease of oxygen in the tumour microenvironment, would normally cause tumour cell death. “However, certain solid tumours have evolved to survive this hostile microenvironment by activating HIF-1α, a gene reported to be a major factor mediating the adaptive response to changes in tissue oxygen level,” explains Dr Janji. William G. Kaelin Jr, Sir Peter J. Ratcliffe and Gregg L. Semenza were awarded the Nobel Prize in Physiology or Medicine in 2019 for their discovery of HIF-1 and how cells use it to sense hypoxia. Hypoxia has also been reported to be responsible for the failure of tumour response to conventional anti-cancer therapies and can prevent the infiltration of immune cells into the tumour. It is therefore crucial to understand the mechanisms by which cancer cells overcome this hypoxic environment to improve the effectiveness of available anti-cancer therapies.

In this context, the team led by Dr Janji sought to inactivate the functionality of the HIF-1α gene using CRISPR gene editing technology and investigate the impact of such inactivation on tumour growth, immune cell infiltration and response to immunotherapy in a preclinical melanoma mouse model.

Our study revealed that blocking the activity of HIF-1α significantly inhibited melanoma growth and amplified the infiltration of immune cells into the tumour microenvironment by increasing the release of CCL5, a well-defined mediator involved in driving cytotoxic immune cells to the tumour battlefield”, summarises Dr Audrey Lequeux, first author of the publication. Importantly, the study also showed that combining a drug devised to stop hypoxia significantly improves melanoma immunotherapy. When the results were validated retrospectively in a cohort of 473 melanoma patients, the hypoxic signature of tumours was correlated to worsened outcomes and the lack of immune cell infiltration into tumours, which is considered as a major characteristic of tumour resistance to immunotherapies.
Together, our data strongly argue that therapeutic strategies disrupting HIF-1α would be able to modulate the tumour microenvironment to permit the infiltration of immune cells. Such strategies could be used to improve vaccine-based and immune checkpoint blockade-based cancer immunotherapies in non-responder melanoma patients,” conclude Dr Chouaib and Dr Janji from Gulf Medical University and Luxembourg Institute of Health, respectively.

The study was published in June in the Oncogene journal, part of the prestigious Nature publishing group, with the full title “Targeting HIF-1 alpha transcriptional activity drives cytotoxic immune effector cells into melanoma and improves combination immunotherapy”. The article was listed under the category of ‘brief communication’, a category reserved for articles of exceptional interest due to their significance and timely contribution to cancer biology.


FUNDING AND RESEARCH TEAMS

This study was supported by grants from FNRS Televie (grants 7.4535.16, 7.6505.18 and n°7.4606.18), the Luxembourg National Research Fund (C18/BM/12670304/COMBATIC and PRIDE15/10675146/CANBIO), the Fondation Cancer, Luxembourg (FC/2018/06), the Kriibskrank Kanner Foundation, Luxembourg, Janssen Cilag Pharma, Roche Pharma, Action LIONS Vaincre le Cancer Luxembourg and Sheik Hamdan Bin Rashid Al Maktoum Foundation (United Arab Emirates). It was performed in close collaboration with national and international partners including the Department of Hemato-oncology at the Centre Hospitalier du Luxembourg, the French National Institute of Health and Medical Research (INSERM), Gustave Roussy Cancer Center, France and the Thumbay Research Institute of Precision Medicine of the Gulf Medical University (UAE).


Reference: Lequeux, A., Noman, M.Z., Xiao, M. et al. Targeting HIF-1 alpha transcriptional activity drives cytotoxic immune effector cells into melanoma and improves combination immunotherapy. Oncogene (2021). https://doi.org/10.1038/s41388-021-01846-x


Provided by Luxembourg Institute of Health

Immunotherapy after Bladder Cancer Surgery May Reduce Recurrence, Study Shows (Medicine)

New research from Memorial Sloan Kettering Cancer Center (MSK) medical oncologist Dean Bajorin, MD, and colleagues found that patients who received nivolumab (Opdivo®) after bladder cancer surgery reduced their overall risk for high-grade bladder cancer recurrence. This research was published today in the New England Journal of Medicine.

In this phase III randomized study, Dr. Bajorin and a team of investigators evaluated 709 patients who were at high risk for recurrence of urothelial cancer after removal of their bladder, ureter, or kidney for high-grade cancer. To evaluate for benefit, patients were randomized to receive either nivolumab or a placebo every two weeks for one year. Patients and physicians were blinded to the treatment. Both safety and quality of life were evaluated.

Dr. Bajorin and investigators found that in high-risk patients, nivolumab reduced recurrence after surgery compared to patients who received the placebo. The current standard of care following surgery that removes the bladder or kidney and ureter has been observation without adjuvant therapy — even in patients at high risk of recurrence and death. This is because no chemotherapy or immunotherapy has previously been shown to be of benefit. Participants who received nivolumab had disease-free survival of 21 months compared with 10.9 months in people receiving the placebo.

“We are very encouraged by the data and the results of the study,” said Dr. Bajorin, first and corresponding author of the study. “Despite available therapies for advanced metastatic bladder cancer, new options are needed to improve long-term disease control and patient survival. These findings have the potential to change the standard of care for bladder cancer.”

Urothelial cancers are tumors that start in the lining of the urine-collecting system that transports urine from the kidneys to the outside of our bodies. These cancers are often referred to as “bladder cancer” because most of them start in the bladder.

Dr. Bajorin and colleagues concluded that the survival data is not yet mature and will need additional research and follow-up. The primary endpoints of disease-free survival in the study population and disease free-survival in the subset of patients with PD-L1-positive tumors were met, and these findings are highly statistically significant and clinically relevant for a population of patients with a clear unmet medical need.

“The trial demonstrates that novel therapies can be identified as having patient benefit when the studies are conducted in a very rigorous fashion. We are hoping this treatment will get approval for all patients at high risk of recurrence after the US Food and Drug Administration has done a detailed review of all the data,” said Dr. Bajorin.

Making Pioneering Advances for Bladder Cancer Patients

Cancer immunotherapy was born at MSK a little over a century ago. Since then, physician-scientists across MSK have led the effort to develop immune-based treatments for different types of cancer. MSK has been at the epicenter of discoveries in the field, and the institution’s work is bringing exciting new treatment options to people around the world. MSK physicians have extensive experience using immunotherapy to treat people with melanoma, kidney cancer, lung cancer, and other cancers as well as handling immune-related side effects.

Without treatment, bladder cancer can be an aggressive disease. In 2021, it is estimated that there will be nearly 17,000 deaths due to bladder cancer in the United States — and numbers are expected to rise significantly in the next decade. 

“As physicians, we consistently strive to provide our patients with the most effective therapies and give those with advanced disease more options,” said Dr. Bajorin.

This trial was sponsored by Bristol Myers Squibb, Checkmate 274.


Reference: Dean F. Bajorin, J. Alfred Witjes, Jürgen E. Gschwend, Michael Schenker, et al., “Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma”, N Engl J Med 2021; 384:2102-2114
DOI: 10.1056/NEJMoa2034442


Provided by MSKCC

Protein Disguise Could Be New Target For Cancer Immunotherapy (Medicine)

Researchers at the Francis Crick Institute have identified a protein that helps tumours evade the immune system and, in certain types of cancers, is linked to a poorer chance of survival. The protein could become a target for future cancer treatments.

A crucial part of the immune system’s response to cancer is a group of white blood cells, called CD8+ T-cells, which kill tumour cells. Before they launch their anti-tumour response, these cells must be told who to attack by another immune cell, called a dendritic cell.

In their study, published in Cell today (2 June), the scientists identified a protein that is present in blood plasma and is also secreted by cancer cells, secreted gelsolin, which interferes with this relay process by blocking a receptor inside dendritic cells. With no instruction passed to the T-cells, the tumours avoid their killer response.

The team analysed clinical data and samples from cancer patients with 10 different types of the disease and found that individuals with liver, head and neck and stomach cancers, who have lower levels of this protein in their tumours had higher chances of survival.*

They also found that blocking the action of this protein in mice with cancer increased their response to treatments including checkpoint inhibitors, a major immunotherapy.

Caetano Reis e Sousa, author and group leader of the Immunobiology Laboratory at the Crick, says: “The interaction between tumour cells, the surrounding environment and the immune system is a complex picture. And although immunotherapies have revolutionised the way certain cancers are treated, there’s still a lot to understand about who is most likely to benefit.

“It’s exciting to find a previously unknown mechanism for how our body recognises and tackles tumours. This opens new avenues for developing drugs that increase the number of patients with different types of cancer who might benefit from innovative immunotherapies.”

This work builds on the team’s research into dendritic cell biology. These cells absorb debris from dead cancer cells and hold them internally in pockets called phagosomes. Binding to a protein on the debris, F-actin, triggers these pockets to burst, releasing the debris into the cell where they can be processed and moved to the surface to signal the presence of a tumour to nearby T-cells.

When the researchers examined the activity of secreted gelsolin, they found the protein outcompetes a key dendritic cell receptor, blocking its ability to bind to F-actin and therefore the ability of the dendritic cells to initiate a T-cell response.

“Dendritic cells play a vital role in the immune system and our body’s response to cancer,” says Evangelos Giampazolias, author and postdoc in the Immunobiology Laboratory at the Crick. “Understanding this process in more detail will enable us to identify how cancers are able to hide and how we might remove their disguise.”

Oliver Schulz, author and research scientist in the of the Immunobiology Laboratory at the Crick says, “While secreted gelsolin circulates in healthy blood plasma, some cancer cells secrete really high levels of it – so these tumours are launching an anti-immune defence which helps them avoid killer T-cells.

“Reducing levels of this protein will help alleviate the competition for binding to F-actin and allow dendritic cells to communicate their vital message.”

The researchers will continue this work, trying to develop a potential therapy that targets the secreted gelsolin in the tumour without affecting the activity of this protein in other parts of the body.


Reference: Giampazolias, E. et al. (2021). Secreted gelsolin inhibits DNGR-1-dependent crosspresentation and cancer immunity. Cell. 10.1016/j.cell.2021.05.021


Provided by Francis Crick Institute