Translational research team to test CAR T-cell therapy for pancreatic cancer

Carl H. June

Stand Up To Cancer, in collaboration with the Lustgarten Foundation for Pancreatic Cancer Research, is supporting a new translational research team that will explore how chimeric antigen receptor T-cell therapy can be applied to pancreatic cancer.

The team is headed by three pioneers in chimeric antigen receptor (CAR) T-cell therapy development at The University of Pennsylvania’s Perelman School of Medicine: Carl H. June, MD, the Richard W. Vague professor in immunotherapy and director of the Center for Cellular Immunotherapies; Shelley L. Berger, PhD, the Daniel S. Och university professor; and E. John Wherry, PhD, the Richard and Barbara Schiffrin president’s distinguished professor of microbiology and director of the Institute for Immunology.

Their research — which will focus largely on the epigenetic state of CAR T cells — will be funded by a $2 million grant from Stand Up To Cancer and the Lustgarten Foundation for Pancreatic Cancer Research.

“We will investigate CAR T-cell therapy for pancreatic cancer in combination with analysis of the epigenetics of patients who respond to the treatment, as well as those who fail to respond, with the goal of finding ways to increase the response rate and explore new therapies against this terrible disease,” June said in a press release. “Identification of mechanisms of resistance is the central question facing the field of immuno-oncology.”

HemOnc Today spoke with June about this research initiative, the timeline for results and the potential clinical implications of the findings.

 

Question: How did the idea for this initiative come about?

Answer: This initiative has taken about 3 years of refining, as the field is so rapidly moving. We wanted to study the resistance or success measures in people treated with CAR T cells. Initially, we proposed to conduct this research in hematologic malignancies. The problem, in the end, was that there is almost no resistance. There is an almost 90% complete remission rate. We then looked at various ways to treat pancreatic cancer with CAR T cells. It turns out we were better positioned to test that. There are no home runs with immunotherapy in pancreatic cancer, so we decided that pancreatic cancer would be a good place to assess next-generation CAR T cells. The technology has become so much better to follow the cells once they are infused into the patient. What is truly different with CAR T cells from other immuno-oncology therapies — such as checkpoint inhibitor therapy — is that it is hard to tell if something works. We can biopsy a tumor but we do not know from those cells which ones really are the ones that we were hoping to have and which ones are bystanders. Conversely, CAR T cells are genetically marked. We can take them back out of a patient and biopsy the blood or tumor and identify the exact cells that were infused into the patient. We can then understand sophisticated and epigenetic changes in that cell. We should be able to correlate that in people who have better responses from those who have no responses. This is where our team is with our work so far.

 

Q: Who is involved?

A: The experts in my group are working with CAR T cells and trying to make next-generational therapies. Another group, led by Jonathan Wherry, PhD, is working on the concept of T-cell exhaustion, which appears to be an issue of major resistance in melanoma and lung cancer. The third team, led by Shelly Berger, PhD, is working on CAR T cells and their epigenetic state.

 

 

Q: What will the initiative entail and what will be tested?

A: We will focus on carrying out early-stage trials with a CAR T cell that targets mesothelin, which is on all pancreatic cancer cells. We have two trials that have just begun. One trial is for patients with ovarian cancer, mesothelioma and lung cancers that express mesothelin. The second trial is looking at the same CAR T cells in patients with metastatic pancreatic cancer. We want to understand the resistance to CAR T-cell therapy and solid tumors and better understand what might be tumor specific tissues vs. general solid tumor tissues. Additionally, we have a number of control populations in which we are doing deep analysis of the immune cell, both in age-matched normal patients and patients with newly diagnosed pancreatic cancer.

 

Q: What is the timeline for results?

A: Within the next 6 months, we expect to have the initial results from patients on the first trial. The pancreatic trial will be about 6 months behind the initial trial. We most likely will have results within 1 year on what may be common between the tumors and what might be distinct to pancreatic cancer. The next phase would be to try engineering around whatever resistance we find.

 

Q: What do you hypothesize that you will find?

A: Pancreatic cancer is set apart from many other cancers in that it does not respond to PD-1 pathway antagonists. In contrast, patients with ovarian cancer do respond to checkpoint therapies. This Stand Up To Cancer trial is a first-in-human trial with CAR T cells for these cancers, so we do not really know what to expect. Therefore, we are using unbiased genome and epigenome-wide analysis of the CAR T cells in patients after infusion, with the intent of identifying characteristics in T cells that have antitumor activity and factors that lead to loss of antitumor activity in CAR T cells.

 

Q: What might the potential clinical implications of the findings be?

A: It could lead us to an improved CAR T cell approach. Additionally, it might teach us to create a combination treatment with a vaccine or checkpoint molecules. These results will definitely inform the next steps, and we will use our results to improve and accelerate the treatment landscape.

 

Q: Is there anything else that you would like to mention?

A: Cancer therapy with CAR T cells has potent results for patients with advanced blood tumors. The major challenge to the field is how to extend this new modality from leukemia to solid tumors, such as pancreatic cancer. Team science approaches have the potential to accelerate progress in this important area of cancer research. – by Jennifer Southall

 

For more information:

Carl H. June, MD, can be reached at The University of Pennsylvania Perelman School of Medicine, 295 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104; email: cjune@upenn.edu.

Disclosure: June reports grant support from Novartis. He also holds intellectual property licensed by The University of Pennsylvania to Novartis.

Carl H. June

Stand Up To Cancer, in collaboration with the Lustgarten Foundation for Pancreatic Cancer Research, is supporting a new translational research team that will explore how chimeric antigen receptor T-cell therapy can be applied to pancreatic cancer.

The team is headed by three pioneers in chimeric antigen receptor (CAR) T-cell therapy development at The University of Pennsylvania’s Perelman School of Medicine: Carl H. June, MD, the Richard W. Vague professor in immunotherapy and director of the Center for Cellular Immunotherapies; Shelley L. Berger, PhD, the Daniel S. Och university professor; and E. John Wherry, PhD, the Richard and Barbara Schiffrin president’s distinguished professor of microbiology and director of the Institute for Immunology.

Their research — which will focus largely on the epigenetic state of CAR T cells — will be funded by a $2 million grant from Stand Up To Cancer and the Lustgarten Foundation for Pancreatic Cancer Research.

“We will investigate CAR T-cell therapy for pancreatic cancer in combination with analysis of the epigenetics of patients who respond to the treatment, as well as those who fail to respond, with the goal of finding ways to increase the response rate and explore new therapies against this terrible disease,” June said in a press release. “Identification of mechanisms of resistance is the central question facing the field of immuno-oncology.”

HemOnc Today spoke with June about this research initiative, the timeline for results and the potential clinical implications of the findings.

 

Question: How did the idea for this initiative come about?

Answer: This initiative has taken about 3 years of refining, as the field is so rapidly moving. We wanted to study the resistance or success measures in people treated with CAR T cells. Initially, we proposed to conduct this research in hematologic malignancies. The problem, in the end, was that there is almost no resistance. There is an almost 90% complete remission rate. We then looked at various ways to treat pancreatic cancer with CAR T cells. It turns out we were better positioned to test that. There are no home runs with immunotherapy in pancreatic cancer, so we decided that pancreatic cancer would be a good place to assess next-generation CAR T cells. The technology has become so much better to follow the cells once they are infused into the patient. What is truly different with CAR T cells from other immuno-oncology therapies — such as checkpoint inhibitor therapy — is that it is hard to tell if something works. We can biopsy a tumor but we do not know from those cells which ones really are the ones that we were hoping to have and which ones are bystanders. Conversely, CAR T cells are genetically marked. We can take them back out of a patient and biopsy the blood or tumor and identify the exact cells that were infused into the patient. We can then understand sophisticated and epigenetic changes in that cell. We should be able to correlate that in people who have better responses from those who have no responses. This is where our team is with our work so far.

 

Q: Who is involved?

A: The experts in my group are working with CAR T cells and trying to make next-generational therapies. Another group, led by Jonathan Wherry, PhD, is working on the concept of T-cell exhaustion, which appears to be an issue of major resistance in melanoma and lung cancer. The third team, led by Shelly Berger, PhD, is working on CAR T cells and their epigenetic state.

 

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Q: What will the initiative entail and what will be tested?

A: We will focus on carrying out early-stage trials with a CAR T cell that targets mesothelin, which is on all pancreatic cancer cells. We have two trials that have just begun. One trial is for patients with ovarian cancer, mesothelioma and lung cancers that express mesothelin. The second trial is looking at the same CAR T cells in patients with metastatic pancreatic cancer. We want to understand the resistance to CAR T-cell therapy and solid tumors and better understand what might be tumor specific tissues vs. general solid tumor tissues. Additionally, we have a number of control populations in which we are doing deep analysis of the immune cell, both in age-matched normal patients and patients with newly diagnosed pancreatic cancer.

 

Q: What is the timeline for results?

A: Within the next 6 months, we expect to have the initial results from patients on the first trial. The pancreatic trial will be about 6 months behind the initial trial. We most likely will have results within 1 year on what may be common between the tumors and what might be distinct to pancreatic cancer. The next phase would be to try engineering around whatever resistance we find.

 

Q: What do you hypothesize that you will find?

A: Pancreatic cancer is set apart from many other cancers in that it does not respond to PD-1 pathway antagonists. In contrast, patients with ovarian cancer do respond to checkpoint therapies. This Stand Up To Cancer trial is a first-in-human trial with CAR T cells for these cancers, so we do not really know what to expect. Therefore, we are using unbiased genome and epigenome-wide analysis of the CAR T cells in patients after infusion, with the intent of identifying characteristics in T cells that have antitumor activity and factors that lead to loss of antitumor activity in CAR T cells.

 

Q: What might the potential clinical implications of the findings be?

A: It could lead us to an improved CAR T cell approach. Additionally, it might teach us to create a combination treatment with a vaccine or checkpoint molecules. These results will definitely inform the next steps, and we will use our results to improve and accelerate the treatment landscape.

 

Q: Is there anything else that you would like to mention?

A: Cancer therapy with CAR T cells has potent results for patients with advanced blood tumors. The major challenge to the field is how to extend this new modality from leukemia to solid tumors, such as pancreatic cancer. Team science approaches have the potential to accelerate progress in this important area of cancer research. – by Jennifer Southall

 

For more information:

Carl H. June, MD, can be reached at The University of Pennsylvania Perelman School of Medicine, 295 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104; email: cjune@upenn.edu.

Disclosure: June reports grant support from Novartis. He also holds intellectual property licensed by The University of Pennsylvania to Novartis.

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