Tag: Car T Cell Therapy

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A Potential Strategy to Improve T Cell Therapy in Solid Tumors

A new Penn Medicine preclinical study demonstrates a simultaneous ‘knockout’ of two inflammatory regulators boosts T cell expansion to attack solid tumors.

by Meagan Raeke

Image: Courtesy of Penn Medicine News

A new approach that delivers a “one-two punch” to help T cells attack solid tumors is the focus of a preclinical study by researchers from the Perelman School of Medicine. The findings, published in the Proceedings of the National Academy of Sciences, show that targeting two regulators that control gene functions related to inflammation led to at least 10 times greater T cell expansion in models, resulting in increased anti-tumor immune activity and durability.

CAR T cell therapy was pioneered at Penn Medicine by Carl H. June, the Richard W. Vague Professor in Immunotherapy at Penn and director of the Center for Cellular Immunotherapies (CCI) at Abramson Cancer Center, whose work led to the first approved CAR T cell therapy for B-cell acute lymphoblastic leukemia in 2017. Since then, personalized cellular therapies have revolutionized blood cancer treatment, but remained stubbornly ineffective against solid tumors, such as lung cancer and breast cancer.

“We want to unlock CAR T cell therapy for patients with solid tumors, which include the most commonly diagnosed cancer types,” says June, the new study’s senior author. “Our study shows that immune inflammatory regulator targeting is worth additional investigation to enhance T cell potency.”

One of the challenges for CAR T cell therapy in solid tumors is a phenomenon known as T cell exhaustion, where the persistent antigen exposure from the solid mass of tumor cells wears out the T cells to the point that they aren’t able to mount an anti-tumor response. Engineering already exhausted T cells from patients for CAR T cell therapy results in a less effective product because the T cells don’t multiply enough or remember their task as well.

Previous observational studies hinted at the inflammatory regulator Regnase-1 as a potential target to indirectly overcome the effects of T cell exhaustion because it can cause hyperinflammation when disrupted in T cells—reviving them to produce an anti-tumor response. The research team, including lead author David Mai, a bioengineering graduate student in the School of Engineering and Applied Science, and co-corresponding author Neil Sheppard, head of the CCI T Cell Engineering Lab, hypothesized that targeting the related, but independent Roquin-1 regulator at the same time could boost responses further.

“Each of these two regulatory genes has been implicated in restricting T cell inflammatory responses, but we found that disrupting them together produced much greater anti-cancer effects than disrupting them individually,” Mai says. “By building on previous research, we are starting to get closer to strategies that seem to be promising in the solid tumor context.”

Read the full story in Penn Medicine News.

June is a member of the Penn Bioengineering Graduate Group. Read more stories featuring June’s research here.

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Carl June and Avery Posey Lead the Way in CAR T Cell Therapy

Perelman School of Medicine (PSOM) professors and Penn Bioengineering Graduate Group members Carl June and Avery Posey are leading the charge in T cell therapy and the fight against cancer.

Avery Posey, PhD
Carl June, MD

Advances in genome editing through processes such as CRISPR, and the ability to rewire cells through synthetic biology, have led to increasingly elaborate approaches for modifying and supercharging T cells for therapy. Avery Posey,  Assistant Professor of Pharmacology, and Carl June, the Richard W. Vague Professor in Immunotherapy, explain how new techniques are providing tools to counter some of the limitations of current CAR T cell therapies in a recent Nature feature.

The pair were also part of a team of researchers from PSOM, the Children’s Hospital of Philadelphia (CHOP), and the Corporal Michael J. Crescenz VA Medical Center to receive an inaugural $8 million Therapy ACceleration To Intercept CAncer Lethality (TACTICAL) Award from the Prostate Cancer Foundation. Their project will develop new clinic-ready CAR T cell therapies for Metastatic Castrate-Resistant Prostate Cancer (mCRPC).

Read “The race to supercharge cancer-fighting T cells” in Nature.

Read about the TACTICAL Award in the December 2022 Awards & Accolades section of Penn Medicine News.

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CAR T Cell Therapy Reaches Beyond Cancer

Penn Medicine researchers laud the early results for CAR T therapy in lupus patients, which point to broader horizons for the use of personalized cellular therapies.

Penn Medicine’s Carl June and Daniel Baker.

Engineered immune cells, known as CAR T cells, have shown the world what personalized immunotherapies can do to fight blood cancers. Now, investigators have reported highly promising early results for CAR T therapy in a small set of patients with the autoimmune disease lupus. Penn Medicine CAR T pioneer Carl June and Daniel Baker, a doctoral student in cell and molecular biology in the Perelman School of Medicine, discuss this development in a commentary published in Cell.

“We’ve always known that in principle, CAR T therapies could have broad applications, and it’s very encouraging to see early evidence that this promise is now being realized,” says June, who is the Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine at Penn Medicine and director of the Center for Cellular Immunotherapies at the Abramson Cancer Center.

T cells are among the immune system’s most powerful weapons. They can bind to, and kill, other cells they recognize as valid targets, including virus-infected cells. CAR T cells are T cells that have been redirected, through genetic engineering, to efficiently kill specifically defined cell types.

CAR T therapies are created out of each patient’s own cells—collected from the patient’s blood, and then engineered and multiplied in the lab before being reinfused into the patient as a “living drug.” The first CAR T therapy, Kymriah, was developed by June and his team at Penn Medicine, and received Food & Drug Administration approval in 2017. There are now six FDA-approved CAR T cell therapies in the United States, for six different cancers.

From the start of CAR T research, experts believed that T cells could be engineered to fight many conditions other than B cell cancers. Dozens of research teams around the world, including teams at Penn Medicine and biotech spinoffs who are working to develop effective treatments from Penn-developed personalized cellular therapy constructs, are examining these potential new applications. Researchers say lupus is an obvious choice for CAR T therapy because it too is driven by B cells, and thus experimental CAR T therapies against it can employ existing anti-B-cell designs. B cells are the immune system’s antibody-producing cells, and, in lupus, B cells arise that attack the patient’s own organs and tissues.

This story is by Meagan Raeke. Read more at Penn Medicine News.

Carl June is a member of the Penn Bioengineering Graduate Group. Read more stories featuring June’s research here.

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2022 Career Award Recipient: Michael Mitchell

by Melissa Pappas

Michael Mitchell (Illustration by Melissa Pappas)

Michael Mitchell, J. Peter and Geri Skirkanich Assistant Professor of Innovation in the Department of Bioengineering, is one of this year’s recipients of the National Science Foundation’s CAREER Award. The award is given to early-career faculty researchers who demonstrate the potential to be role models in their field and invest in the outreach and education of their work.

Mitchell’s award will fund research on techniques for “immunoengineering” macrophages. By providing new instructions to these cells via nanoparticles laden with mRNA and DNA sequences, the immune system could be trained to target and eliminate solid tumors. The award will also support graduate students and postdoctoral fellows in his lab over the next five years.

The project aligns with Mitchell’s larger research goals and the current explosion of interest in therapies that use mRNA, thanks to the technological breakthroughs that enabled the development of COVID-19 vaccines.

“The development of the COVID vaccine using mRNA has opened doors for other cell therapies,” says Mitchell. “The high-priority area of research that we are focusing on is oncological therapies, and there are multiple applications for mRNA engineering in the fight against cancer.”

A new wave of remarkably effective cancer treatments incorporates chimeric antigen receptor T-cell (CAR-T) therapy. There, a patient’s T-cells, a type of white blood cell that fights infections, are genetically engineered to identify, target and kill individual cancer cells that accumulate in the circulatory system.

However, despite CART-T therapy’s success in treating certain blood cancers, the approach is not effective against cancers that form solid tumors. Because T-cells are not able to penetrate tumors’ fibrous barriers, Mitchell and his colleagues have turned to another part of the immune system for help.

Read the full story in Penn Engineering Today.

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Penn Medicine CAR T Therapy Expert Carl June Receives 2022 Keio Medical Science Prize

by Brandon Lausch

The award from Japan’s oldest private university honors outstanding contributions to medicine and life sciences.

Richard W. Vague Professor in Immunotherapy Carl June.

Carl June, the Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine in the Perelman School of Medicine and director of the Center for Cellular Immunotherapies at Penn’s Abramson Cancer Center, has been named a 2022 Keio Medical Science Prize Laureate. He is recognized for his pioneering role in the development of CAR T cell therapy for cancer, which uses modified versions of patients’ own immune cells to attack their cancer.

The Keio Medical Science Prize is an annual award endowed by Keio University, Japan’s oldest private university, which recognizes researchers who have made an outstanding contribution to the fields of medicine or the life sciences. It is the only prize of its kind awarded by a Japanese university, and eight laureates of this prize have later won the Nobel Prize. Now in its 27th year, the prize encourages the expansion of researcher networks throughout the world and contributes to the well-being of humankind.

“Dr. June exemplifies the spirit of curiosity and fortitude that make Penn home to so many ‘firsts’ in science and medicine,” said Penn President Liz Magill. “His work provides hope to cancer patients and their families across the world, and inspiration to our global community of physicians and scientists who are working to develop the next generation of treatments and cures for diseases of all kinds.”

Read the full story in Penn Today.

June is a member of the Penn Bioengineering Graduate Group. Read more stories featuring June’s research here.

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Penn Startup Vittoria Biotherapeutics Raises $10M in Seed Funding

Marco Ruella, MD

A Philadelphia life sciences company spun out of Penn is emerging from stealth mode with nearly $10 million from a seed funding round. Vittoria Biotherapeutics’ mission is to overcome limitations of CAR T cell therapy by using unique cell engineering and gene editing technologies to create new therapies that address unmet clinical needs. The technology the company is attempting to commercialize was developed by Marco Ruella, M.D., Assistant Professor of Medicine in the Perelman School of Medicine and member of the Penn Bioengineering Graduate Group, who is the company’s scientific founder.

Read “Penn spinout Vittoria Biotherapeutics emerges from stealth mode with $10M seed round” in the Philadelphia Business Journal.

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Penn Medicine and Children’s Hospital of Philadelphia Announce Partnership with Costa Rica for CAR T Cell Therapy

Carl June, MD

Carl June, MD, Professor in the Perelman School of Medicine and member of the Penn Bioengineering Graduate Group, was quoted in a recent press release  announcing a new international partnership between Penn Medicine (PSOM), the Children’s Hospital of Pennsylvania (CHOP), and Costa Rica’s CCSS, or the Caja Costarricense de Seguro Social (Social Security Program), to develop CAR T research in Costa Rica. June is a world renowned cancer cell therapy pioneer whose research led to the initial development and FDA approval of CAR T cell therapy:

“‘At least 15,000 patients across the world have received CAR T cells, and dozens more clinical trials using this approach are in progress, for almost every major tumor type, but people in many parts of the globe still do not have access to treatment with these transformative therapies,’ said Carl H. June, MD, the Richard W. Vague Professor in Immunotherapy and director of the Center for Cellular Immunotherapies in Penn’s Perelman School of Medicine. “We are honored to work with our colleagues in Costa Rica in hopes of building a path for patients in underserved areas to have the opportunity to benefit from clinical research programs offering this personalized therapy.’”

Read the the announcement in Penn Medicine News.

 

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FDA Approves Penn Pioneered CAR T Cell Therapy for Third Indication

The U.S. Food and Drug Administration has expanded its approval for Kymriah, a personalized cellular therapy developed at the Abramson Cancer Center, this time for the treatment of adults with relapsed/refractory follicular lymphoma who have received at least two lines of systemic therapy. “Patients with follicular lymphoma who relapse or don’t respond to treatment have a poor prognosis and may face a series of treatment options without a meaningful, lasting response,” said Stephen J. Schuster, the Robert and Margarita Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and Lymphoma in the Division of Hematology Oncology. It’s the third FDA approval for the “living drug,” which was the first of its kind to be approved, in 2017, and remains the only CAR T cell therapy approved for both adult and pediatric patients.

“In just over a decade, we have moved from treating the very first patients with CAR T cell therapy and seeing them live healthy lives beyond cancer to having three FDA-approved uses of these living drugs which have helped thousands of patients across the globe,” said Carl June, MD, the Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine in Penn’s Perelman School of Medicine and director of the Center for Cellular Immunotherapies in the Abramson Cancer Center and director of the Parker Institute for Cancer Immunotherapy at Penn. “Today’s news is new fuel for our work to define the future of cell therapy and set new standards in harnessing the immune system to treat cancer.”

Research from June, a member of the Penn Bioengineering Graduate Group, led to the initial FDA approval for the CAR T therapy (sold by Novartis as Kymriah) for treating acute lymphoblastic leukemia (ALL), one of the most common childhood cancers.

Read the full announcement in Penn Medicine News.

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Exploring the History of CAR-T Cell Therapy

Carl June, MD

A new feature in Chemistry World explores the history of CAR (chimeric antigen receptor)-T cell therapy, a revolutionary type of therapeutic treatment for certain types of cancer. One of the pioneers of CAR-T cell therapy is Carl June, Richard W. Vague Professor in Immunotherapy in the Perelman School of Medicine and member of the Penn Bioengineering Graduate Group. His groundbreaking research opened the door for FDA approval of the CAR T therapy called Kymriah, which treats acute lymphoblastic leukemia (ALL), one of the most common childhood cancers.

Read “A decade of CAR-T cell therapy” in Chemistry World.

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Decade-long Remission After CAR T Cell Therapy

Bill Ludwig, left, was the first patient to receive CAR T cells as part of clinical trials at Abramson Cancer Center. Carl June, right, has played a pioneering roll in the therapeutic use of CAR T cells. (Image: Penn Medicine)

Carl H. June, the Richard W. Vague Professor in Immunotherapy in Pathology and Laboratory Medicine at Penn Medicine, director of the Center for Cellular Immunotherapies and the Parker Institute for Cancer Immunotherapy, and member of the Penn Bioengineering Graduate Group at the University of Pennsylvania, has led a new analytical study published in Nature that explains the longest persistence of CAR T cell therapy recorded to date against chronic lymphocytic leukemia (CLL), and shows that the CAR T cells remained detectable at least a decade after infusion, with sustained remission in both patients. June’s pioneering work in gene therapy led to the FDA approval for the CAR T therapy (sold by Novartis as Kymriah) for treating leukemia and transforming the fight against cancer. His lab develops new forms of T cell based therapies.

Read the story in Penn Today