Tag Archives: Immunotherapy

Microbiology

University of Louisville researchers receive $5.8 million to prevent immune system dysregulation

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Reviewed by Megan Craig, M.Sc.Jun 2 2023

Researchers at the University of Louisville have received $5.8 million in two grants from the National Institutes of Health to expand their work to better understand and prevent immune system dysregulation responsible for acute respiratory distress, the condition responsible for serious illness and death in some COVID-19 patients. A separate $306,000 NIH Small Business Innovation Research grant supports early testing of a compound developed at UofL as a potential treatment.

The three grants combined total $6.1 million.

During the pandemic, health care providers worked tirelessly to treat patients who became seriously ill with COVID-19. Some of those patients developed severe lung disease known as acute respiratory distress syndrome (ARDS) due to an excessive response of the immune system often called cytokine storm.

As they treated these critically ill patients, physicians and other providers at UofL Health shared their clinical insights and patient samples with researchers at UofL to discover the cause of the immune system overresponse.

At one time we had over 100 patients with COVID in the hospital. Once they were on a ventilator, mortality was about 50%. We were looking at this issue to see why some people would do well while some developed bad lung disease and did not do well or died.”

Jiapeng Huang, an anesthesiologist with UofL Health and professor and vice chair of the Department of Anesthesiology and Perioperative Medicine in the UofL School of Medicine

The UofL researchers, led by immunologist Jun Yan, discovered that a specific type of immune cells, low-density inflammatory neutrophils, became highly elevated in some COVID-19 patients whose condition became very severe. This elevation signaled a clinical crisis point and increased likelihood of death within a few days due to lung inflammation, blood clotting and stroke. Their findings were published in 2021 in JCI Insight.

With the new NIH funding, Yan is leading research to build on this discovery with deeper understanding of what causes a patient’s immune system to respond to an infection in this way and develop methods to predict, prevent or control the response.

“Through this fruitful collaboration, we now have acquired NIH funding for basic and translational studies and even progress toward commercialization of a potential therapy,” Yan said. “That’s why we do this research – eventually we want to benefit the patients.”

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Yan, chief of the UofL Division of Immunotherapy in the Department of Surgery, a professor of microbiology and immunology and a senior member of the Brown Cancer Center, will lead the new research, along with Huang and Silvia M. Uriarte, university scholar and professor in the Department of Oral Immunology and Infectious Diseases in the UofL School of Dentistry.

“COVID-19 continues to spotlight the impactful synergy between the clinical and research teams at the University of Louisville,” said Jason Smith, UofL Health chief medical officer. “Innovation is in the DNA of academic medicine. We collaborate to provide each patient the best options for prevention and treatment today, while developing the even better options for tomorrow.”

In addition to two research grants of $2.9 million each awarded directly to UofL, a $306,000 grant to a startup company will support early testing of a compound developed in the lab of UofL Professor of Medicine Kenneth McLeish that shows promise in preventing the dangerous cytokine storm while allowing the neutrophils to retain their ability to kill harmful bacteria and viruses. The compound, DGN-23, will be tested by UofL and Degranin Therapeutics, a startup operated by McLeish, Yan, Huang, Uriarte and Madhavi Rane, associate professor in the Department of Medicine.

“This is one more example of how UofL has led the charge in finding new and innovative ways to detect, contain and fight COVID-19 and other potential public health threats,” said Kevin Gardner, UofL’s executive vice president for research and innovation. “This team’s new research and technology could help keep people healthy and safe here and beyond.”

The knowledge gained through these studies may benefit not only COVID-19 patients, but those with other conditions in which immune dysregulation can occur, such as other types of viral and bacterial pneumonia and autoimmune diseases, and patients undergoing cancer immunotherapy and organ transplantation.

The grants

Grant 1 – $2.9 million, four-year grant to UofL. Investigators will study the new subset of neutrophils Yan identified to better understand how they contribute to acute respiratory distress and clotting. They also will determine whether a novel compound will prevent these complications. They will use lab techniques and studies with animal models that allow for manipulation of certain conditions that cannot be done in human subjects.

Grant 2 – $2.9 million, five-year grant to UofL. This work examines a more comprehensive landscape to characterize different subsets of neutrophils and measure their changes over the course of COVID-19 disease progression and how neutrophils contribute to immune dysfunction.

Grant 3 – $306,000, one-year grant to Degranin Therapeutics and UofL for early testing of DGN-23, a compound developed at UofL, to determine its effectiveness in preventing or reducing immune dysregulation.

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Source:

University of Louisville

Microbiology

STING Like a Bee: MIT’s Revolutionary Approach to Cancer Immunotherapy

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A cancer vaccine combining checkpoint blockade therapy and a STING-activating drug eliminates tumors and prevents recurrence in mice.

MIT researchers have engineered a therapeutic cancer vaccine that targets the STING pathway, vital for immune response to cancer cells. This vaccine has shown significant potential in eliminating tumors, inhibiting metastasis, and preventing recurrence in mouse models of different cancers, with minimal side effects. The treatment is even effective in cases where the STING gene is mutated. The study also revealed an unexpected key role of CD4+ T cells in antitumor immunity.

Immune checkpoint blockade therapies have been revolutionary in the treatment of some cancer types, emerging as one of the most promising treatments for diseases such as melanoma, colon cancer, and non-small cell lung cancer.

While in some cases checkpoint blockade therapies elicit a strong immune response that clears tumors, checkpoint inhibitors do not work for all tumor types or all patients. Moreover, some patients who do experience an initial benefit from these therapies see their cancers recur. Only a small minority of patients treated with checkpoint blockade therapies see lasting benefits. Researchers have developed various combination therapy strategies to overcome resistance to checkpoint blockade therapies, with the STING pathway emerging as one of the most attractive lines of inquiry.

In a study published recently in the journal Advanced Healthcare Materials, a team of MIT researchers engineered a therapeutic cancer vaccine capable of restoring STING signaling and eliminating the majority of tumors in mouse models of colon cancer and melanoma, with minimal side effects. The vaccine also inhibited metastasis in a breast cancer mouse model and prevented the recurrence of tumors in cured mice.

“We have repurposed a naturally existing adaptor protein into a novel, dual-functional cancer vaccine that initiates and sustains an effective antitumoral immunity. The protein complex stimulated robust immune attack and helped form long-term memory against tumors in mouse models of colon cancer and melanoma,” says Angela Belcher, the senior author of the study, a member of the Koch Institute for Integrative Cancer Research, and the head of MIT’s Department of Biological Engineering.

The study was led by MIT postdoc Yanpu He and conducted in collaboration with the laboratory of Paula Hammond, who is also a member of the Koch Institute, an MIT Institute Professor, and the head of MIT’s Department of Chemical Engineering. Other authors of the paper include Celestine Hong, Shengnan Huang, Justin Kaskow, Gil Covarrubias, Ivan Pires, and James Sacane.

Building blocks of a vaccine

Immune checkpoints are a key part of a system that helps the immune system tell the difference between the body’s own healthy cells and threats such as harmful bacteria or cancer cells. When checkpoint proteins on the surface of immune cells bind to partner proteins on other cells, the interaction gives rise to a signal that prevents T cells and other immune cells from mounting an attack. By presenting the same type of partner proteins, cancer cells can evade destruction by the immune system. Immune checkpoint blockade therapies — the discovery of which was recognized by the 2018 Nobel Prize in Physiology or Medicine — work by binding to partner proteins on cancer cells and allowing the immune system to respond.

The STING pathway holds promise as a partner for immune checkpoint blockade therapies because of its key role in raising immune response to pathogens and cancer cells. The pathway is also known to impact the immune system in other ways, including the maturation, specialization, and activation of certain types of immune cells.

Although there are multiple ongoing clinical trials that combine an immune checkpoint blockade with a STING-targeted therapy, few have obtained approval from the U.S. Food and Drug Administration, largely because they can cause serious toxic and inflammatory side effects when administered systemically. Side effects can be limited by injecting STING directly into the tumor, but this strategy still leaves one serious challenge unanswered: Nineteen percent of people carry mutated versions of the STING gene and do not respond to STING-targeted therapies.

In past work, the researchers worked to address this challenge by engineering a protein complex capable of restoring STING signaling in cell lines that lacked STING protein or had a mutated and ineffective version of the gene. The complex combined a piece of the STING protein responsible for triggering the downstream signaling with cGAMP, a small molecule that stimulates the STING pathway.

In the present study, the team added one more component to the STING-cGAMP complex: a smaller form of an antibody known as a nanobody carrying immune checkpoint blockade therapy.

After direct injection into tumors, the cancer vaccine eliminated 70-100 percent of tumors in mouse models of colon cancer and melanoma. The researchers found that most of the vaccine remained within the tumor and that treated mice lost minimal weight, suggesting that the risk of systemic side effects is low. Cured mice remained tumor-free after six months of observation, and when researchers rechallenged the mice with tumor cells to simulate cancer recurrence, 100 percent of those mice rejected them through immune memory. When mice whose STING genes were inactivated were treated, the vaccine still restored STING signaling and significantly reduced the size of tumors, although not as effectively as in mice with normal STING function.

“With further development, this platform not only promises to increase the effectiveness of checkpoint blockade therapies and prevent recurrence for cancer patients more broadly,” Belcher says, “but it may lead to a novel cancer treatment that could make checkpoint blockade therapy viable for large fraction of the human population with loss-of-function STING mutations.”

A surprising role for CD4+ T cells

When the researchers investigated the mechanisms of tumor response to the vaccine, they found — contrary to their expectations — that a subtype of T cells called CD4+ T cells played a pivotal role in achieving antitumor immunity.

In clinical cancer treatments, CD4+ T cells play various roles in the immune system and are usually associated with immunosuppression. Subsequently, most research on checkpoint blockade therapies and the STING pathway has centered on other types of immune cells whose roles in raising immune responses are better understood — for instance, natural killer cells and CD8+ T cells, both of which are responsible for attacking tumor cells. The importance of CD4+ cells has only been recently discovered for immune checkpoint blockade therapies, while their role in STING signaling has only been investigated in cell lines or in the context of preventive and not therapeutic vaccines.

Researchers found that the cancer vaccine changed how CD4+ T cells behaved in tumors. After depleting different populations of immune cells, the researchers tracked how the tumors responded after treatment. While depleting macrophage and natural killer cells only partially compromised the effectiveness of the vaccine, CD8+ T cells were predictably essential. However, CD4+ T cells were likewise indispensable. Without CD4+ T cells, tumors treated with the vaccine behaved as if they received no treatment at all.

CD4+ T cells can develop into several different subtypes with different functions. In tumors, CD4+ T cells frequently develop into the regulatory T (Treg) subtype that suppresses immune response. But with the cancer vaccine, researchers found that STING signaling polarized the CD4+ T cells into the T helper Type I (TH1) phenotype, a helper T cell that activates other immune cells to attack tumor cells.

“A key to leveraging CD4+ T cells in cancer therapies may be in understanding how they are polarized and activated,” says He. “Mechanistic insights from this study could inform future work on CD4+ T cells, allowing researchers to unlock the significant therapeutic potential of these cells for human cancer patients.”

Researchers believe that their approach could be developed into a modular platform, using different types of immune checkpoint blockade therapies. In future work, they plan to fine-tune their therapeutic strategy to improve potential outcomes for patients who carry STING mutations, for example by adjusting the dosage and timing of treatment and exploring the use of other nanobodies to engage immune cells.

Reference: “STING Protein-Based In Situ Vaccine Synergizes CD4+ T, CD8+ T, and NK Cells for Tumor Eradication” by Yanpu He, Celestine Hong, Shengnan Huang, Justin A. Kaskow, Gil Covarrubias, Ivan S. Pires, James C. Sacane, Paula T. Hammond and Angela M. Belcher, 4 April 2023, Advanced Healthcare Materials.
DOI: 10.1002/adhm.202300688

The study was supported in part by the Koch Institute Frontier Research Program and the Marble Center for Cancer Nanomedicine.

Bendta Schroeder. MIT Koch Institute

Microbiology

First-in-human nanoparticle HIV vaccine induces broad and publicly targeted helper T cell responses

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Reviewed by Lily Ramsey, LLMMay 25 2023

Researchers from Fred Hutchinson Cancer Center in Seattle, Scripps Research in La Jolla, California, IAVI and other collaborating institutions have characterized robust T-cell responses in volunteers participating in the IAVI G001 Phase 1 clinical trial to test the safety and immune response of a self-assembling nanoparticle HIV vaccine.

Their work, published in Science Translational Medicine, signals a major step toward development of a vaccine approach to end the HIV/AIDS epidemic worldwide. The antigen used in this study was jointly developed by IAVI and Scripps Research and has been shown in previous analyses to stimulate VRC01-class B cells, an immune response considered promising enough for boosting in further studies.

We were quite impressed that this vaccine candidate produced such a vigorous T-cell response in almost all trial participants who received the vaccine. These results highlight the potential of this HIV-1 nanoparticle vaccine approach to induce the critical T-cell help needed for maturing antibodies toward the pathway of broadly neutralizing against HIV.”

Julie McElrath, MD, PhD, senior vice president and director of Fred Hutch’s Vaccine and Infectious Disease Division and co-senior author of the study

However, she added, this is the first step, and heterologous booster vaccines will still be needed to eventually produce VRC01-class broadly neutralizing antibodies, which in previous studies have demonstrated the ability to neutralize approximately 90% of HIV strains.

“We showed previously that this vaccine induced the desired B-cell responses from HIV broadly neutralizing antibody precursors. Here we demonstrated strong CD4 T-cell responses, and we went beyond what is normally done by drilling down to identify the T cell epitopes and found several broadly immunogenic epitopes that might be useful for developing boosters and for other vaccines,” William Schief, PhD, executive director of vaccine design for IAVI’s Neutralizing Antibody Center at Scripps Research and professor, Department of Immunology and Microbiology, at Scripps Research, who is co-senior author of the study.

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The trial is a phase 1, randomized, double-blind and placebo-controlled study to evaluate the safety and effectiveness of a nanoparticle HIV vaccine in healthy adult volunteers without HIV. It was comprised of two groups with 18 vaccine and six placebo recipients per group, with 48 total enrollees. Participants were given two doses of the vaccine or placebo eight weeks apart.

McElrath acknowledged the groundbreaking work of her lab team, the biostatistical team and Fred Hutch’s Vaccine Trials Unit for their invaluable contributions to the study. The Vaccine Trials Unit conducts multiple vaccine trials and was one of only two sites for this study.

Findings from the study include:

  • Vaccine-specific CD4 T cells were induced in almost all vaccine recipients.
  • Lymph node GC T follicular helper cells increased after vaccination compared to placebo.
  • Lumazine synthase protein, needed for self-assembly of the particle, also induced T-cell responses that can provide additional help to ultimately enhance efficacy in a sequential vaccine strategy.
  • Vaccine-specific CD4 T cells were polyfunctional and had diverse phenotypes.
  • LumSyn-specific CD8 T cells were highly polyfunctional and had a predominantly effector memory phenotype.
  • CD4 T-cell responses were driven by immunodominant epitopes with diverse and promiscuous HLA restriction.
  • CD8 T-cell responses to LumSyn were driven by HLA-A*02-restricted immunodominant epitopes B- and T-cell responses correlated within but not between LN and peripheral blood compartments.

This study was funded by the Bill & Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery; IAVI Neutralizing Antibody Center; National Institute of Allergy and Infectious Diseases; and Ragon Institute of MGH, MIT and Harvard.

Study authors WRS and SM are inventors on a patent filed by Scripps and IAVI on the eOD-GT8 monomer and 60-mer immunogens (patent number 11248027, “Engineered outer domain (eOD) of HIV gp 120 and mutants thereof”). WRS, KWC and MJM are inventors on patents filed by Scripps, IAVI and Fred Hutch on immunodominant peptides from LumSyn (Title: Immunogenic compositions; filing no. 63127975).

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Source:

Fred Hutchinson Cancer Center

Journal reference:

Cohen, K. W., et al. (2023) A first-in-human germline-targeting HIV nanoparticle vaccine induced broad and publicly targeted helper T cell responses. Science Translational Medicine. doi.org/10.1126/scitranslmed.adf3309.

Microbiology

Novel computational platform can expand the pool of cancer immunotherapy targets

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Reviewed by Megan Craig, M.Sc.May 17 2023

Researchers at Children’s Hospital of Philadelphia (CHOP) and the University of California, Los Angeles (UCLA) have developed a computational platform capable of discovering tumor antigens derived from alternative RNA splicing, expanding the pool of cancer immunotherapy targets. The tool, called “Isoform peptides from RNA splicing for Immunotherapy target Screening” (IRIS), was described in a paper published today in the Proceedings of the National Academy of Sciences.

Immunotherapy has revolutionized cancer treatment, but for many cancers including pediatric cancers, the repertoire of antigens is incomplete, underscoring a need to expand the inventory of actionable immunotherapy targets. We know that aberrant alternative RNA splicing is widespread in cancer and generates a range of potential immunotherapy targets. In our study, we were able to show that our computational platform was able to identify immunotherapy targets that arise from alternative splicing, introducing a broadly applicable framework for discovering novel cancer immunotherapy targets that arise from this process.”

Yi Xing, PhD, co-senior author, director of the Center for Computational and Genomic Medicine at CHOP

Cancer immunotherapy has ushered in a sea change in the treatment of many hematologic cancers, harnessing the power of a patient’s own immune system to fight the disease. Chimeric antigen receptor T-cell (CAR-T) and T cell receptor-engineered T cell (TCR-T) therapies modify a patient’s own T cells to attack known antigens on the surface of cancer cells and have often led to durable responses for cancers that were once considered incurable. However, the field has encountered challenges in the solid tumor space, in large part due to a lack of known and suitable targets for these cancers, highlighting the need for novel approaches to expand the pool of immunotherapy targets.

Alternative splicing is an essential process that allows for one gene to code for many gene products, based on where the RNA is cut and joined, or spliced, before being translated into proteins. However, the splicing process is dysregulated in cancer cells, which often take advantage of this process to produce proteins that promote growth and survival, allowing them to replicate uncontrollably and metastasize. This happens in many adult and pediatric cancers. Scientists have suggested splicing dysregulation could be a source of novel tumor antigens for immunotherapy, but identifying such antigens has been a challenge.

To address this difficulty, the researchers created IRIS to leverage large-scale tumor and normal RNA sequencing data and incorporate multiple screening approaches to discover tumor antigens that arise due to alternative splicing. Integrating RNA sequencing-based transcriptomics data and mass spectrometry-based proteomics data, the researchers showed that hundreds of IRIS-predicted TCR targets are presented by human leukocyte antigen (HLA) molecules, the part of the human immune system that presents antigens to T cells.

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The researchers then applied IRIS to RNA sequencing data from neuroendocrine prostate cancer (NEPC), a metastatic and highly lethal disease known to involve shifts in RNA splicing, as discovered in a prior study by CHOP and UCLA researchers. From 2,939 alternative splicing events enriched in NEPC, IRIS predicted 1,651 peptides as potential TCR targets. The researchers then applied a more stringent screening test, which prioritized 48 potential targets. Interestingly, the researchers found that these targets were highly enriched for peptides encoded by short sequences of less than 30 nucleotides in length – also known as “microexons” – which may arise from a unique program of splicing dysregulation in this type of cancer.

To validate the immunogenicity of these targets, the researchers isolated T cells reactive to IRIS-predicted targets, and then used single-cell sequencing to identify the TCR sequences. The researchers modified human peripheral blood mononuclear cells with seven TCRs and found they were highly reactive against targets predicted by IRIS to be good immunotherapy candidates. One TCR was particularly efficient at killing tumor cells expressing the target peptide of interest.

“Immunotherapy is a powerful tool that has had a significant impact on the treatment of some cancers, but the benefits have not been fully realized in many lethal cancers that could benefit from this approach,” said Owen N. Witte, MD, University Professor of Microbiology, Immunology, and Molecular Genetics and member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “The discovery of new antigenic targets that may be shared among different patients – and even different tumor types – could be instrumental in expanding the value of cell-based therapies. Analyzing massive amounts of data on tumor and normal tissues, which requires sophisticated computational tools like those developed by the Xing Lab, provides actionable insights on targets that one day could be tested in the clinic.”

“This proof-of-concept study demonstrates that alternatively spliced RNA transcripts are viable targets for cancer immunotherapy and provides a big data and multiomics-powered computational platform for finding these targets,” Dr. Xing added. “We are applying IRIS for target discovery across a wide range of pediatric and adult cancers. We are also developing a next-generation IRIS platform that harnesses newer transcriptomics technologies, such as long read and single cell analysis.”

This research was supported in part by the Immuno-Oncology Translational Network (IOTN) of the National Cancer Institute’s Cancer Moonshot Initiative, other National Institutes of Health funding, the Parker Institute for Cancer Immunotherapy, the Cancer Research Institute, and the Ressler Family Fund.

Source:

Children’s Hospital of Philadelphia

Journal reference:

Pan, Y., et al. (2023) IRIS: Discovery of cancer immunotherapy targets arising from pre-mRNA alternative splicing. PNAS. doi.org/10.1073/pnas.2221116120.

Microbiology

New Vaccine Helps Decrease the Likelihood of Skin Cancer Recurrence and Death

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A recent clinical trial reveals that the combination of an experimental mRNA vaccine with an immunotherapy led to a 44% decrease in the risk of melanoma recurrence or death compared to the use of immunotherapy alone.

The randomized phase 2b trial, which was headed by researchers at NYU Langone Health and its Perlmutter Cancer Center, included both men and women who underwent surgery for the removal of melanoma from their lymph nodes or other organs and were at a heightened risk of the disease reappearing at distant sites from the original cancer.

Among 107 study subjects who were injected with both the experimental vaccine, called mRNA-4157/V940, and the immunotherapy pembrolizumab, the cancer returned in 24 subjects (22.4%) within two years of follow-up, compared with 20 out of 50 (40%) who received only pembrolizumab.

“Our phase 2b study shows that a neoantigen mRNA vaccine, when used in combination with pembrolizumab, resulted in prolonged time without recurrence or death compared with pembrolizumab alone,” said study senior investigator Jeffrey Weber, MD, Ph.D., the deputy director of the Perlmutter Cancer Center.

The phase 2b trial results are to be presented at the annual meeting of the American Association for Cancer Research on April 16 in Orlando, Florida.

While randomized phase 3 trials test whether a treatment is superior to current standard therapies, phase 2 trials like the current study provide preliminary reassurance that one treatment is likely to be better than another, and lead to larger studies to confirm those results. Phase 3 trials of the combination of the mRNA-4157/V940 vaccine with pembrolizumab versus pembrolizumab alone are already planned at NYU Langone and a number of other medical centers globally, said Weber, the Laura and Isaac Perlmutter Professor of Oncology in the Department of Medicine at NYU Grossman School of Medicine.

Study results so far led the United States Food and Drug Administration in February to grant Breakthrough Therapy Designation to mRNA-4157/V940 in combination with pembrolizumab, a designation designed to speed government reviews of trial results.

The current results highlight the role of immune system T cells capable of attacking viruses as well as cancers. To spare normal cells, this system uses “checkpoint” molecules on T cell surfaces to “turn off” their attack against viruses when they clear the infection. The body may recognize tumors as abnormal, but cancer cells hijack checkpoints to turn off, evade and avoid immune responses. Immunotherapies like pembrolizumab seek to block checkpoints, making cancer cells more “visible” and vulnerable again to immune cells.

Immunotherapies have become the mainstay for treating melanoma, although they do not work for all patients because melanoma cells, known for their ability to evade the immune system, can become resistant to immunotherapy. For this reason, researchers have looked at adding vaccines. While most vaccines used today are designed to prevent infections, they can also be tailored to target proteins involved in cancer.

Like the COVID-19 vaccine, mRNA-4157/V940 is based on messenger RNA, a chemical cousin of DNA that provides instructions to cells for making proteins. mRNA cancer vaccines are designed to teach the body’s immune system to recognize cancer cells as different from normal cells. In designing a vaccine against melanoma, researchers attempted to trigger an immune response to specific abnormal proteins, called “neoantigens,” made by cancer cells.

Because the study volunteers all had their tumors removed, researchers were able to analyze their cells for neoantigens that were specific to each melanoma and create a “personalized” vaccine for each patient. As a result, T cells were produced specific to the neoantigen proteins encoded by the mRNA. Those T cells could then attack any melanoma cells trying to grow or spread.

Scientists involved in the study say that the personalized mRNA-4157/V940 vaccine took about six to eight weeks to develop for each patient and could recognize as many as 34 neoantigens. Severe side effects were similar between the two arms of the study, they said, with fatigue being the most common side effect specific to the vaccine reported by patients.

Watch a video with researcher and patient commentary here.

Meeting: AACR Annual Meeting 2023

The study was presented at the annual meeting of the American Association for Cancer Research on Sunday, April 16, 2023, at 11 a.m. EDT in Orlando, Fla., and was titled “A personalized cancer vaccine, mRNA-4157, combined with pembrolizumab in patients with resected high-risk melanoma: Efficacy and safety results from the randomized, open-label Phase 2b mRNA-4157-P201/Keynote-942 trial.

The study was funded by Moderna Inc. of Cambridge, Mass., and Merck of Rahway, NJ. mRNA-4157/V940 is being jointly developed and commercialized by Moderna and Merck. Merck is the manufacturer of pembrolizumab. About 1.3 million Americans are currently diagnosed with some form of melanoma.

Weber consults for and has received less than $10,000 per annum from Merck, Genentech, Astra Zeneca, GSK, Novartis, Nektar, Celldex, Incyte, Biond, Moderna, ImCheck, Sellas, Evaxion, Pfizer, Regeneron, and EMD Serono; has received $10-25,000 from BMS for membership on Advisory Boards; he holds equity in Biond, Evaxion, OncoC4, and Instil Bio; and is on scientific advisory boards for CytoMx, Incyte, ImCheck, Biond, Sellas, Instil Bio, OncoC4, and Neximmune, for which he is remunerated between $10,000-$50,000 dollars. He is not a member of any speaker’s bureau; NYU received research support from BMS, Merck, GSK, Moderna, Pfizer, Novartis, and Astra Zeneca; Weber is one of the co-authors on two patents filed by Moffitt Cancer Center and one patent filed by Biodesix and receives less than $6,000 yearly in royalties. These relationships are being managed in accordance with the policies and practices of NYU Langone Health.

Besides Weber, other study co-investigators are Adnan Khattak, at Hollywood Private Hospitals in Nedlands, Australia; Matteo Carlino, at Westmead Hospital in Westmead, Australia; Tarek Meniawy, at Saint John of God Subiaco Hospital in Subiaco, Australia; George Ansstas, at Washington University in St. Louis, Mo.; Teresa Medina, at University of Colorado in Aurora; Matthew Taylor, at the Earle A. Chiles Research Institute in Portland, Ore.; Kevin Kim, at California Pacific Medical Center Research Institute in Oakland; Meredith McKean, at the Sarah Cannon Research Institute in Nashville, Tenn.; Georgina Long, at Melanoma Institute Australia in Wollstonecraft, Australia; Ryan Sullivan, at Mass General Brigham in Boston; Mark Faries, at The Angeles Clinic and Research Institute in Los Angeles; Thuy Tran, at Yale-New Haven Hospital in New Haven, Conn.; Charles Cowey, at Baylor Scott & White Charles A. Sammons Cancer Center in Dallas; Andrew Pecora, at the John Thuerer Cancer Center in Hackensack, NJ; Jennifer Segar, at the University of Arizona in Tucson; Victoria Atkinson, at Princess Alexandra Hospital in Woolloongabba, Australia; Geoffrey Gibney, at Lombardi Cancer Center in Washington, DC; Jason Luke, at the University of Pittsburgh in Pennsylvania; Sajeve Thomas, at Orlando Health in Florida; Elizabeth Buckbinder, at Dana-Farber Cancer Institute in Boston; Peijie Hou, Lili Zhu, Michelle Brown, Praveen Aanur, and Robert Meehan, at Moderna Inc. in Cambridge, Mass.; and Tal Zaks, at OrbiMed in New York City.

NYU Langone Health / NYU Grossman School of Medicine

Microbiology

Leaving lymph nodes intact until after immunotherapy could boost efficacy against solid tumors

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Reviewed by Emily Henderson, B.Sc.Mar 20 2023

Cancer treatment routinely involves taking out lymph nodes near the tumor in case they contain metastatic cancer cells. But new findings from a clinical trial by researchers at UC San Francisco and Gladstone Institutes shows that immunotherapy can activate tumor-fighting T cells in nearby lymph nodes.

The study, published March 16, 2023 in Cell, suggests that leaving lymph nodes intact until after immunotherapy could boost efficacy against solid tumors, only a small fraction of which currently respond to these newer types of treatments.

Most immunotherapies are aimed only at reinvigorating T cells in the tumor, where they often become exhausted battling the tumor’s cancer cells. But the new research shows that allowing the treatment to activate the immune response of the lymph nodes as well can play an important role in driving positive response to immunotherapy.

This work really changes our thinking about the importance of keeping lymph nodes in the body during treatment.”

Matt Spitzer, PhD, investigator for the Parker Institute for Cancer Immunotherapy and Gladstone-UCSF Institute of Genomic Immunology and senior author of the study

Lymph nodes are often removed because they are typically the first place metastatic cancer cells appear, and without surgery, it can be difficult to determine whether the nodes contain metastases.

“Immunotherapy is designed to jump start the immune response, but when we take out nearby lymph nodes before treatment, we’re essentially removing the key locations where T cells live and can be activated,” Spitzer said, noting that the evidence supporting the removal of lymph nodes is from older studies that predate the use of today’s immunotherapies.

Aim for the lymph nodes, not the tumor

Researchers have largely been working under the assumption that cancer immunotherapy works by stimulating the immune cells within the tumor, Spitzer said. But in a 2017 study in mice, Spitzer showed that immunotherapy drugs are actually activating the lymph nodes.

“That study changed our understanding of how these therapies might be working,” said Spitzer. Rather than the immunotherapy pumping up the T cells in the tumor, he said, T cells in the lymph nodes are likely the source for T cells circulating in the blood. Such circulating cells can then go into the tumor and kill off the cancer cells.

Having shown that intact lymph nodes can temper cancer’s hold in mice, Spitzer’s team wanted to know whether the same would prove true in human patients. They chose to design a trial for patients with head and neck cancers because of the high number of lymph nodes in those areas.

The trial enrolled 12 patients whose tumors hadn’t yet metastasized past the lymph nodes. Typically, such patients would undergo surgery to remove the tumor, followed by other treatments if recommended.

Instead, patients received a single cycle of an immunotherapy drug called atezolizumab (anti-PD-L1) that is produced by Genentech, a sponsor of the trial. A week or two later, Spitzer’s team measured how much the treatment activated the patients’ immune systems.

The treatment also included surgically removing each patient’s tumor and nearby lymph nodes after immunotherapy and analyzing how the immunotherapy affected them.

The team found that, after immunotherapy, the cancer-killing T cells in the lymph nodes began springing into action. They also found higher numbers of related immune cells in the patients’ blood.

Spitzer attributes some of the trial’s success to its design, which allowed the team to get a lot of information from a small number of patients by looking at the tissue before and after surgery and running detailed analyses.

“Being able to collect the tissue from surgery shortly after the patients had been given the drug was a really unique opportunity,” he said. “We were able to see, at the cellular level, what the drug was doing to the immune response.”

That kind of insight would be challenging to get from a more traditional trial in patients with later-stage disease, who would not typically benefit from undergoing surgery after immunotherapy.

Metastases inhibit immune response

Another benefit of the study design was that it allowed researchers to compare how the treatment affected lymph nodes with and without metastases, or a second cancer growth.

“No one had looked at metastatic lymph nodes in this way before,” said Spitzer. “We could see that the metastases impaired the immune response relative to what we saw in the healthy lymph nodes.”

It could be that the T cells in these metastatic nodes were less activated by the therapy, Spitzer said. If so, that could explain, in part, the poor performance of some immunotherapy treatments.

Still, the therapy prompted enough T-cell activity in the metastatic lymph nodes to consider leaving them in for a short period of time until treatment ends. “Removing lymph nodes with metastatic cancer cells is probably still important but taking them out before immunotherapy treatment may be throwing the baby out with the bathwater,” said Spitzer.

A subsequent goal of the current trial is to determine whether giving immunotherapy before surgery protects against the recurrence of tumors in the future. Researchers won’t know the answer to that until they’ve had a chance to monitor the participants for several years.

“My hope is that if we can activate a good immune response before the tumor is taken out, all those T cells will stay in the body and recognize cancer cells if they come back,” Spitzer said.

Next, the team plans to study better treatments for patients with metastatic lymph nodes, using drugs that would be more effective at reactivating their immune responses.

Source:

University of California – San Francisco

Journal reference:

Rahim, M. K., et al. (2023). Dynamic CD8+ T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes. Cell. doi.org/10.1016/j.cell.2023.02.021

Microbiology

Decreased viral infection severity in females may be due to extra copy of X chromosome-linked gene

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Reviewed by Emily Henderson, B.Sc.Mar 17 2023

It has long been known that viral infections can be more severe in males than females, but the question as to why has remained a mystery – until possibly now. The key may lie in an epigenetic regulator that boosts the activity of specialized anti-viral immune cells known as natural killer (NK) cells.

In a study published March 16 in the peer-reviewed journal Nature Immunology, a collaborative team of UCLA researchers have found that female mouse and human NK cells have an extra copy of an X chromosome-linked gene called UTX. UTX acts as an epigenetic regulator to boost NK cell anti-viral function, while repressing NK cell numbers.

While it is well-known that males have more NK cells compared to females, we did not understand why the increased number of NK cells was not more protective during viral infections. It turns out that females have more UTX in their NK cells than do males, which allows them to fight viral infections more efficiently.”

Dr. Maureen Su, co-senior author, professor of microbiology immunology and molecular genetics, and of pediatrics, at the David Geffen School of Medicine at UCLA

The researchers noted that this held true whether or not the mice had gonads (ovaries in females; testes in males), indicating that the observed trait was not linked to hormones. Furthermore, female mice with lower UTX expression had more NK cells which were not as capable of controlling viral infection.

“This implicates UTX as a critical molecular determinant of sex differences in NK cells,” said the study’s lead author Mandy Cheng, graduate student in molecular biology at UCLA.

The findings suggest that therapies involving immune responses need to move beyond a “one-size-fits-all” approach and toward a precision medicine model, also known as personalized medicine, that tailors treatments that take into account people’s individual differences, such as genetics, environment and other factors that influence health and disease risk, the researchers write.

“Given the recent excitement with using NK cells in the clinic, we will need to incorporate sex as a biological factor in treatment decisions and immunotherapy design,” said co-senior author Tim O’Sullivan, assistant professor of microbiology, immunology and molecular genetics at the Geffen School.

Source:

University of California – Los Angeles Health Sciences

Journal reference:

Cheng, M.I., et al. (2023) The X-linked epigenetic regulator UTX controls NK cell-intrinsic sex differences. Nature Immunology. doi.org/10.1038/s41590-023-01463-8.

Microbiology

Healthy gut bacteria can travel to other parts of the body and boost antitumor immunity

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Reviewed by Emily Henderson, B.Sc.Mar 9 2023

Researchers at UT Southwestern Medical Center have discovered how healthy bacteria can escape the intestine, travel to lymph nodes and cancerous tumors elsewhere in the body, and boost the effectiveness of certain immunotherapy drugs. The findings, published in Science Immunology, shed light on why antibiotics can weaken the effect of immunotherapies and could lead to new cancer treatments.

Scientists have been stumped as to how bacteria inside your gut can have an impact on a cancer in your lungs, breasts, or skin. Now we understand that mechanism much better and, in the future, hope to use this knowledge to better fight cancer.”

Andrew Y. Koh, M.D., Associate Professor of Pediatrics, Microbiology, and in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern

Previous studies, including one led by Dr. Koh at UT Southwestern, have shown an association between the composition of gut microbiomes – the microorganisms found inside the digestive tract – and the effectiveness of cancer treatments that target the immune system, including pembrolizumab (Keytruda) and ipilimumab (Yervoy). However, researchers have reached conflicting conclusions about the ideal balance of microorganisms to optimize therapy, with studies pointing to different beneficial bacteria.

Dr. Koh and colleagues used mice with melanoma tumors to probe how the drugs, called immune checkpoint inhibitors, affected the movement of gut microbes through the body. They found that immune checkpoint inhibitors, which boost the activity of the immune system against tumors, also cause inflammation in the digestive system that leads to remodeling of lymph nodes in the gut.

Due to these changes, bacteria can leave the intestines and travel to lymph nodes near the tumor and the tumor itself, the researchers found. Here, the microbes activate a set of immune cells that act to kill tumor cells.

“Immune checkpoint inhibitors work by releasing the brakes on the immune system to target cancer,” said Dr. Koh, who is also Director of the Cellular and ImmunoTherapeutics Program at UTSW and Children’s Health. “What we think is that these microorganisms and the immune cells they’re activating are essentially pressing on the accelerator of the immune system at the same time.”

The findings suggest that a course of antibiotics, which can eliminate most gut microbes, is detrimental to immune checkpoint inhibitors because the bacteria can no longer play this role of immune accelerant. It also helps explain why researchers have found many types of bacteria in patient microbiomes that seem to be beneficial for treatment.

“As long as a subset of beneficial bacteria can translocate from the gut to the lymph node or tumor, it may not matter exactly which bacteria it is,” said Dr. Koh.

Dr. Koh’s team is now working toward the development of bacterial-based treatments to boost the efficacy of immune checkpoint inhibitors.

Other UTSW researchers who contributed to the study include first author and UTSW graduate student Yongbin Choi, Lora Hooper, Jake Lichterman, Laura Coughlin, Nicole Poulides, Wenling Li, Priscilla Del Valle, Suzette Palmer, Shuheng Gan, Jiwoong Kim, Xiaowei Zhan, Yajing Gao, and Bret Evers.

Dr. Hooper, a Howard Hughes Medical Institute Investigator, holds the Jonathan W. Uhr, M.D. Distinguished Chair in Immunology and is a Nancy Cain and Jeffrey A. Marcus Scholar in Medical Research, in honor of Dr. Bill S. Vowell.

The research was supported by funding from the National Institutes of Health (R01 CA231303, K24 AI123163, R01 DK070855), the Crow Family Fund, the UT Southwestern Medical Center and Children’s Health Cellular and ImmunoTherapeutics Program, National Research Service Award-Integrative Immunology Training Grant (5T32AI005284-43), The Welch Foundation (I-1874), and the Howard Hughes Medical Institute.

Source:

UT Southwestern Medical Center

Journal reference:

Choi, Y., et al. (2023) Immune checkpoint blockade induces gut microbiota translocation that augments extraintestinal antitumor immunity. Science Immunology. doi.org/10.1126/sciimmunol.abo2003.

Microbiology

Genes encoding T cell receptors vary greatly between persons and populations, study reveals

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Reviewed by Emily Henderson, B.Sc.Feb 16 2023

Researchers from Karolinska Institutet have discovered that the genes encoding our T cell receptors vary greatly between persons and populations, which may explain why we respond differently to for example infections. The findings, presented in the journal Immunity, also demonstrate that some gene variants are inherited from Neanderthals.

T-cells that are part of our immune system are central in the protection against infections and cancer. With the help of TCRs, the cells recognize foreign invaders and tumor cells.

“It was previously unknown how variable human TCR genes are”, says Gunilla Karlsson Hedestam, professor at the department of microbiology, tumor and cell biology at Karolinska Institutet and the study’s lead author.

Using deep sequencing of blood samples, the researchers examined TCR genes in 45 people originating from sub-Saharan Africa, East Asia, South Asia and Europe. The researchers showed that these genes vary greatly between different persons and population groups. The results were confirmed by analyses of several thousand additional cases from the 1000 Genomes project.

We found that every individual, other than identical twins, has a unique set of TCR gene variants. These differences reveal possible mechanisms underlying the wide range of responses to infections and vaccines that we observe at the population level.”

Martin Corcoran, first author of the study

“We discovered 175 new gene variants, which doubles the number of known TCR gene variants. An unexpected and surprising finding is that certain gene variants originate from Neanderthals and one of these is present in up to 20% of modern humans in Europe and Asia.”

Gunilla Karlsson Hedestam explains that the variation in these genes cannot be detected with the standard methods used in whole genome sequencing, but with the development of specialized deep sequencing methods and analysis software that allow highly precise definition of B- and T-cell receptor genes, this is now possible.

“As these genes are among the most variable in our genome, the results also provide new information about how our immune system has developed over the course of history, says Martin Corcoran. We are particularly interested in uncovering the function of the TCR variants we have inherited from Neanderthal ancestors. The frequency of these variants in modern humans suggests an advantageous function in our biology and we are keen to understand this”, adds Martin Corcoran.

The findings and the new TCR gene database the researchers now publish can be of great importance in the development of new therapeutic approaches in the future.

“Understanding human genetics is fundamental for the development of targeted treatments. The methods described in the study provide new opportunities, not the least in the cancer field where T-cells are central to several promising forms of immunotherapy”, says Gunilla Karlsson Hedestam.

The results can also shed light on other areas of research.

“The findings can lead to the development of new diagnostics and therapies in a range of medical disciplines, including precision medicine”, says Gunilla Karlsson Hedestam.

What is the next step in your research?

“We are now investigating the functional significance of several of the newly discovered gene variants and how this variation impacts our T-cell responses. We are also planning extended studies involving large groups of individuals to examine the role of TCR gene variation in diseases we know involve T cells, such as infectious diseases, cancer, and autoimmune disorders”, says Gunilla Karlsson Hedestam.

Main funding for the study comes from an ERC Advanced Grant and the Swedish Research Council.

Source:

Karolinska Institutet

Journal reference:

Corcoran, M., et al. (2023) Archaic humans have contributed to large-scale variation in modern human T cell receptor genes. Immunity. doi.org/10.1016/j.immuni.2023.01.026.

Microbiology

Researchers find a way to block anaphylaxis caused by peanut allergies

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Reviewed by Emily Henderson, B.Sc.Feb 9 2023

Researchers from Indiana University School of Medicine have found a way to block anaphylaxis caused by peanut allergies. The groundbreaking discovery could lead to life-saving therapeutics for people with severe peanut allergies.

There are treatments for symptoms in patients with food allergies, but few preventive therapies other than strict dietary avoidance or oral immunotherapy. Neither of those options is successful in all patients.”

Mark Kaplan, PhD, chair of the Department of Microbiology and Immunology and senior author of the study

The team details their findings in a newly published article in Science Translational Medicine. When someone is allergic to a food, it is a result of allergen proteins cross-linking allergen specific immunoglobulin E (IgE) on the surface of mast cells and basophils. Activation of these cells can lead to anaphylaxis, a severe, life-threatening allergic reaction that can occur very quickly after exposure to an allergen.

Researchers developed peanut-specific inhibitors called covalent heterobivalent inhibitor (cHBI), that successfully blocked mast cell or basophil degranulation and anaphylaxis in an animal model.

“The inhibitor prevented allergic reactions for more than two weeks when given before allergen exposure,” said Nada Alakhras, lead author and a graduate student in the Department of Biochemistry and Molecular Biology. “The inhibitor also prevented fatal anaphylaxis and attenuated allergic reactions when given soon after the onset of symptoms.”

“These new findings suggest that cHBI has the potential to be an effective preventative for peanut-specific allergic responses in patients,” said Basar Bilgicer, PhD, professor of chemical and biomedical engineering at the University of Notre Dame and co-senior author of the study.

The inhibitor has not been tested in human patients yet. Researchers are now doing further testing in animal models to evaluate efficacy and toxicity before moving to clinical trials.

The research was funded in part by the Falk Medical Research Trust Award. Other authors include Anthony L. Sinn, Wenwu Zhang, PhD, MS, and Karen E. Pollok, PhD from IU School of Medicine as well as Gyoyeon Hwang, Jenna Sjoerdsma, Emily K. Bromley, and Jaeho Shin from the University of Notre Dame and Scott A. Smith, MD, PhD from Vanderbilt University Medical Center.

Source:

Indiana University School of Medicine

Journal reference:

Alakhras, N.S., et al. (2023) Peanut allergen inhibition prevents anaphylaxis in a humanized mouse model. Science Translational Medicine. doi.org/10.1126/scitranslmed.add6373.