Feature

Intersection of radiotherapy, immunotherapy guides Penn’s new cancer research center

Andy J. Minn, MD, PhD
Andy J. Minn

The Abramson Cancer Center at the University of Pennsylvania has been awarded a $12 million grant from the Mark Foundation for Cancer Research to investigate the complementary potential of radiotherapy and immunotherapy for the treatment of cancer.

The grant will be used to establish the Mark Foundation Center for Immunotherapy, Immune Signaling, and Radiation at University of Pennsylvania. Andy J. Minn, MD, PhD, associate professor of radiation oncology at the university’s Perelman School of Medicine, has been named director of the center.

Minn will lead a multidisciplinary team that will explore the relationship of radiation therapy, signaling pathways among cancer and immune cells, and the immune system’s cancer-fighting capabilities.

The center will begin work on five separate preclinical research projects it hopes will translate into clinical practice. University of Pennsylvania investigators who will lead the projects include: Junwei Shi, PhD; E. John Wherry, PhD; Nancy Zhang, PhD; Jorge Henao-Mejia, MD, PhD; Roger Greenberg, MD, PhD; Sara Cherry, PhD; Constantinos Koumenis, PhD; Igor Brodsky, PhD; and Carl June, MD.

The key objective of the center is to improve cancer treatment, and specifically the effectiveness of immunotherapy.

“We want to focus on whether interferon and pattern recognition receptor signaling can play a potentially pivotal role in cancer treatment,” Minn told HemOnc Today.

Interferon helps the immune system fight infection and viruses; it is typically thought to inhibit the growth of cancer cells and kill them. Pattern recognition receptors are specialized receptors in the immune system that detect pathogens and bacteria when they enter the body.

“The unexpected finding over the last several years is that a lot of different cancer therapies, in particular radiation, also activate interferon and pattern recognition receptor pathways, almost as if mimicking a virus,” Minn said. Research at the center, he noted, will aim to study if and how radiotherapy can use the same pathways that viruses use to trigger and alert the immune system.

“If it turns out that radiation and other cancer therapies do the same thing, then there is a strong rationale for combining immunotherapy with conventional therapies like radiation and chemotherapy,” he said.

The center also will focus on combining novel forms of radiation therapy with immunotherapy to improve overall response to treatment.

The first new form of radiotherapy the center will examine is called FLASH radiation, which delivers an entire course of radiation in less than a second and in preclinical studies has been shown to have comparable efficacy and fewer side effects when compared with traditional radiotherapy, Minn said.

The center has planned five initial research projects, all of which are initially focused on basic, preclinical science, he added.

“We are also going to focus on how to translate our ideas into clinical practice,” Minn said. “An important objective is to translate this research in a short period of time.”

Atypical research

The Mark Foundation Center aims to take a broad approach toward examining the interaction between immune pathways and radiotherapy, with no plans to focus on a single disease.

“Our plan is to study multiple types of cancer, starting with the cancers that already show a response to immunotherapies followed by those that rarely respond to it,” Minn said. “We want to cover a spectrum of different cancers and stages of disease.”

When asked what makes the research the center will conduct novel, he replied that many researchers are studying aspects of interferon and pattern recognition receptor pathways in cancer; however, a critical part of the center’s focus on these pathways is atypical, according to Minn.

“Our scientific perspective on interferon and pattern recognition receptor pathways is a little out of the ordinary,” he said. “Our focus seeks to understand important complexities.”

Minn said it’s commonly accepted that the pathways must be activated to elicit a response from the immune system, and one of the atypical aspects of his team’s research will include understanding how the pathways can also exert inhibitory effects on the immune system.

“This pathway has two faces — it has a stimulatory side and a suppressive side,” he explained. This suggests there are ways to manipulate the pathway to both elicit response and to block resistance to immunotherapies.

“These pathways, when they are activated, can also have inhibitory effects that shut down the immune response, and cancer can take advantage of the suppressive side of this pathway,” he added.

Working on FLASH-y CARs

Led by Carl June, the University of Pennsylvania is a pioneer in chimeric antigen receptor T-cell therapy, and the center hopes to apply what it learns about the interaction of radiotherapy and immune system signaling to the groundbreaking cell-based therapy to increase its effectiveness.

Minn said researchers hope that by understanding how novel forms of radiation like FLASH radiation can activate the immune system, this will provide valuable insight into how to improve CAR T-cell therapy.

“After we better understand the mechanism of the underlying biology, we want to engineer CAR T cells to activate the same pathways that make radiation therapy, potentially like FLASH, effective at activating the immune system,” he said.

Treatment of solid tumors is an area where CAR T has had less success, and the group led by June and Minn hopes it can address this challenge.

It’s about “waking up” the immune system to alert it to cancer’s presence, Minn proclaimed, and using one modality’s effectiveness at fighting the disease to strengthen another in what amounts to a battle on multiple fronts.

“We think that if we can understand the biology behind the wake-up and alert process within the immune system, then we can engineer a CAR T cell to do the same thing and make it work more effectively,” Minn concluded. – by Drew Amorosi

For more information:

Andy J. Minn, MD, PhD, can be reached at Abramson Family Cancer Research Institute, 421 Curie Blvd., BRB II/III, Room 510, Philadelphia, PA 19104; email: andyminn@upenn.edu.
References:

NIH. NCI dictionary of cancer terms. Available at: www.cancer.gov/publications/dictionaries/cancer-terms. Accessed on July 3, 2019.

Zaru R. Pattern recognition receptor (PRRs) ligands. Available at: www.immunology.org/public-information/bitesized-immunology/receptores-y-mol%C3%A9culas/pattern-recognition-receptor-prrs. Accessed on July 3, 2019.

Disclosures: Minn reports research funding from Incyte and Merck; honoraria and travel support from AstraZeneca, Merck, Pfizer and Takeda; and is an inventor on patents related to the IFN pathway and an inventor on a filed patent related to modified CAR T cells.

Andy J. Minn, MD, PhD
Andy J. Minn

The Abramson Cancer Center at the University of Pennsylvania has been awarded a $12 million grant from the Mark Foundation for Cancer Research to investigate the complementary potential of radiotherapy and immunotherapy for the treatment of cancer.

The grant will be used to establish the Mark Foundation Center for Immunotherapy, Immune Signaling, and Radiation at University of Pennsylvania. Andy J. Minn, MD, PhD, associate professor of radiation oncology at the university’s Perelman School of Medicine, has been named director of the center.

Minn will lead a multidisciplinary team that will explore the relationship of radiation therapy, signaling pathways among cancer and immune cells, and the immune system’s cancer-fighting capabilities.

The center will begin work on five separate preclinical research projects it hopes will translate into clinical practice. University of Pennsylvania investigators who will lead the projects include: Junwei Shi, PhD; E. John Wherry, PhD; Nancy Zhang, PhD; Jorge Henao-Mejia, MD, PhD; Roger Greenberg, MD, PhD; Sara Cherry, PhD; Constantinos Koumenis, PhD; Igor Brodsky, PhD; and Carl June, MD.

The key objective of the center is to improve cancer treatment, and specifically the effectiveness of immunotherapy.

“We want to focus on whether interferon and pattern recognition receptor signaling can play a potentially pivotal role in cancer treatment,” Minn told HemOnc Today.

Interferon helps the immune system fight infection and viruses; it is typically thought to inhibit the growth of cancer cells and kill them. Pattern recognition receptors are specialized receptors in the immune system that detect pathogens and bacteria when they enter the body.

“The unexpected finding over the last several years is that a lot of different cancer therapies, in particular radiation, also activate interferon and pattern recognition receptor pathways, almost as if mimicking a virus,” Minn said. Research at the center, he noted, will aim to study if and how radiotherapy can use the same pathways that viruses use to trigger and alert the immune system.

“If it turns out that radiation and other cancer therapies do the same thing, then there is a strong rationale for combining immunotherapy with conventional therapies like radiation and chemotherapy,” he said.

The center also will focus on combining novel forms of radiation therapy with immunotherapy to improve overall response to treatment.

The first new form of radiotherapy the center will examine is called FLASH radiation, which delivers an entire course of radiation in less than a second and in preclinical studies has been shown to have comparable efficacy and fewer side effects when compared with traditional radiotherapy, Minn said.

PAGE BREAK

The center has planned five initial research projects, all of which are initially focused on basic, preclinical science, he added.

“We are also going to focus on how to translate our ideas into clinical practice,” Minn said. “An important objective is to translate this research in a short period of time.”

Atypical research

The Mark Foundation Center aims to take a broad approach toward examining the interaction between immune pathways and radiotherapy, with no plans to focus on a single disease.

“Our plan is to study multiple types of cancer, starting with the cancers that already show a response to immunotherapies followed by those that rarely respond to it,” Minn said. “We want to cover a spectrum of different cancers and stages of disease.”

When asked what makes the research the center will conduct novel, he replied that many researchers are studying aspects of interferon and pattern recognition receptor pathways in cancer; however, a critical part of the center’s focus on these pathways is atypical, according to Minn.

“Our scientific perspective on interferon and pattern recognition receptor pathways is a little out of the ordinary,” he said. “Our focus seeks to understand important complexities.”

Minn said it’s commonly accepted that the pathways must be activated to elicit a response from the immune system, and one of the atypical aspects of his team’s research will include understanding how the pathways can also exert inhibitory effects on the immune system.

“This pathway has two faces — it has a stimulatory side and a suppressive side,” he explained. This suggests there are ways to manipulate the pathway to both elicit response and to block resistance to immunotherapies.

“These pathways, when they are activated, can also have inhibitory effects that shut down the immune response, and cancer can take advantage of the suppressive side of this pathway,” he added.

Working on FLASH-y CARs

Led by Carl June, the University of Pennsylvania is a pioneer in chimeric antigen receptor T-cell therapy, and the center hopes to apply what it learns about the interaction of radiotherapy and immune system signaling to the groundbreaking cell-based therapy to increase its effectiveness.

Minn said researchers hope that by understanding how novel forms of radiation like FLASH radiation can activate the immune system, this will provide valuable insight into how to improve CAR T-cell therapy.

“After we better understand the mechanism of the underlying biology, we want to engineer CAR T cells to activate the same pathways that make radiation therapy, potentially like FLASH, effective at activating the immune system,” he said.

PAGE BREAK

Treatment of solid tumors is an area where CAR T has had less success, and the group led by June and Minn hopes it can address this challenge.

It’s about “waking up” the immune system to alert it to cancer’s presence, Minn proclaimed, and using one modality’s effectiveness at fighting the disease to strengthen another in what amounts to a battle on multiple fronts.

“We think that if we can understand the biology behind the wake-up and alert process within the immune system, then we can engineer a CAR T cell to do the same thing and make it work more effectively,” Minn concluded. – by Drew Amorosi

For more information:

Andy J. Minn, MD, PhD, can be reached at Abramson Family Cancer Research Institute, 421 Curie Blvd., BRB II/III, Room 510, Philadelphia, PA 19104; email: andyminn@upenn.edu.
References:

NIH. NCI dictionary of cancer terms. Available at: www.cancer.gov/publications/dictionaries/cancer-terms. Accessed on July 3, 2019.

Zaru R. Pattern recognition receptor (PRRs) ligands. Available at: www.immunology.org/public-information/bitesized-immunology/receptores-y-mol%C3%A9culas/pattern-recognition-receptor-prrs. Accessed on July 3, 2019.

Disclosures: Minn reports research funding from Incyte and Merck; honoraria and travel support from AstraZeneca, Merck, Pfizer and Takeda; and is an inventor on patents related to the IFN pathway and an inventor on a filed patent related to modified CAR T cells.

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