Feature

CAR T-cell therapy may be effective for colorectal cancer

Adam Snook

Chimeric antigen receptor T-cell therapy may be an effective treatment strategy for colorectal cancer, according to study results.

Adam Snook, PhD, assistant professor in the department of pharmacology and experimental therapeutics at Thomas Jefferson University, and colleagues observed the efficacy of CAR T-cell therapy for treating tumors and preventing metastases among mice. These findings laid the groundwork for a trial designed to assess the approach among humans.

“The antigen we target for colorectal cancer is one that is shared across several high-mortality cancers, including esophageal and pancreatic cancer,” Snook, also a researcher at Sidney Kimmel Cancer Center at Jefferson Health, said in a press release. “Taken together, 25% of people who die from cancer could potentially be treated with this therapy.”

HemOnc Today spoke with Snook about why CAR T-cell therapy may be an effective strategy for colorectal cancer, as well as how the human trials will be conducted.

 

Question: Can you explain the rationale for why CAR T-cell therapy may work in colorectal cancer?

Answer: Two things support CAR T-cell-based therapies in colon cancer. Studies conducted about 10 years ago supported the idea that patients who have tumors containing T cells have better outcomes. Similar findings have been reported from other tumors types. There appears to be a long-term antitumor effect. The other important set of data from humans is where researchers took colon cancer out of humans, isolated T cells from their tumors, grew them in a petri dish in the lab and then put them back into the patient. The T cells eliminated all of their metastases. There is a truly potent effect when T cells are inserted into patients. The paradox here is that colon cancer does not respond to the other available immunotherapies, such as checkpoint inhibitors, and we are unsure why this is so.

 

Q: What CAR T-cell research has already been conducted in this area?

A: There are a variety of different antigens that researchers are testing in colon cancer. For example, carcinoembryonic antigen is found in a lot of colon cancers, as well as many other cancers. Researchers are assessing this but there does appear to be a lot of toxicities associated with it. There are also studies looking at the antigen MUC1, which is also found in a variety of cancers. There are a variety of different antigens that researchers have been testing, but without great success so far.

 

Q: Can you describe the outcomes you observed when you assessed this approach in mice?

A: This is the second half of a bigger research program. In the first half, we published a paper a couple years ago where we developed guanylyl cyclase C (GCC) T cells from mice and gave them to mice. We found they could eliminate tumors that expressed GCC, and they did not cause any toxicities. This was the first proof of concept that this approach could be safe and effective. The CAR T cells that we designed and created in that study could not be used for humans, so we generated new CAR constructs that targeted human GCC and put them into mice with tumors that expressed human GCC, either because we engineered them to or because we used human colon cancer cells. We found they could eliminate the tumor and were associated with a significant survival benefit. All of the mice studied survived without side effects for the duration of the 75-day observation period, compared with a 30-day average survival for mice with control treatment.

Q: What is next in terms of research?

A: The next steps are to optimize and finalize our approach for modifying human T cells. We think there may be some opportunity for improving our approach, but we also want to move the approach from mice to humans. We need to find sponsorship for a clinical trial and move our research to a phase 1 human trial.

 

Q: What do you envision as the most appropriate way to design such a trial?

A: There are a few different approaches. The first may be to figure out how to dose these CAR T cells. So, instead of giving a lot of them at once, one could give smaller amounts spread out over a shorter period of time. Also, building in a ‘kill switch’ can be another approach.

 

Q: In broad terms, what are the potential implications if CAR T-cell therapy is proven to be effective for colorectal cancer specifically, and other solid tumors in general?

A: There are very few effective therapies for advanced-stage colorectal cancer. If we can translate the positive effect observed with leukemias to the advanced-stage colon cancer area, this can have a significant impact on these patients. Approximately 50,000 people die of colon cancer annually in the United States. We could potentially make a dramatic impact here. – by Jennifer Southall

 

Reference:

Magee MS, et al. Cancer Immunol Res. 2018;doi:10.1158/2326-6066.CIR-16-0362.

For more information:

Adam Snook, PhD, can be reached at Thomas Jefferson University and Jefferson Health, 1020 Locust St., Suite 368, Philadelphia, PA 19107; email: adam.snook@jefferson.edu

Disclosure: Snook reports no relevant financial disclosures.

Adam Snook

Chimeric antigen receptor T-cell therapy may be an effective treatment strategy for colorectal cancer, according to study results.

Adam Snook, PhD, assistant professor in the department of pharmacology and experimental therapeutics at Thomas Jefferson University, and colleagues observed the efficacy of CAR T-cell therapy for treating tumors and preventing metastases among mice. These findings laid the groundwork for a trial designed to assess the approach among humans.

“The antigen we target for colorectal cancer is one that is shared across several high-mortality cancers, including esophageal and pancreatic cancer,” Snook, also a researcher at Sidney Kimmel Cancer Center at Jefferson Health, said in a press release. “Taken together, 25% of people who die from cancer could potentially be treated with this therapy.”

HemOnc Today spoke with Snook about why CAR T-cell therapy may be an effective strategy for colorectal cancer, as well as how the human trials will be conducted.

 

Question: Can you explain the rationale for why CAR T-cell therapy may work in colorectal cancer?

Answer: Two things support CAR T-cell-based therapies in colon cancer. Studies conducted about 10 years ago supported the idea that patients who have tumors containing T cells have better outcomes. Similar findings have been reported from other tumors types. There appears to be a long-term antitumor effect. The other important set of data from humans is where researchers took colon cancer out of humans, isolated T cells from their tumors, grew them in a petri dish in the lab and then put them back into the patient. The T cells eliminated all of their metastases. There is a truly potent effect when T cells are inserted into patients. The paradox here is that colon cancer does not respond to the other available immunotherapies, such as checkpoint inhibitors, and we are unsure why this is so.

 

Q: What CAR T-cell research has already been conducted in this area?

A: There are a variety of different antigens that researchers are testing in colon cancer. For example, carcinoembryonic antigen is found in a lot of colon cancers, as well as many other cancers. Researchers are assessing this but there does appear to be a lot of toxicities associated with it. There are also studies looking at the antigen MUC1, which is also found in a variety of cancers. There are a variety of different antigens that researchers have been testing, but without great success so far.

 

Q: Can you describe the outcomes you observed when you assessed this approach in mice?

A: This is the second half of a bigger research program. In the first half, we published a paper a couple years ago where we developed guanylyl cyclase C (GCC) T cells from mice and gave them to mice. We found they could eliminate tumors that expressed GCC, and they did not cause any toxicities. This was the first proof of concept that this approach could be safe and effective. The CAR T cells that we designed and created in that study could not be used for humans, so we generated new CAR constructs that targeted human GCC and put them into mice with tumors that expressed human GCC, either because we engineered them to or because we used human colon cancer cells. We found they could eliminate the tumor and were associated with a significant survival benefit. All of the mice studied survived without side effects for the duration of the 75-day observation period, compared with a 30-day average survival for mice with control treatment.

 

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Q: What is next in terms of research?

A: The next steps are to optimize and finalize our approach for modifying human T cells. We think there may be some opportunity for improving our approach, but we also want to move the approach from mice to humans. We need to find sponsorship for a clinical trial and move our research to a phase 1 human trial.

 

Q: What do you envision as the most appropriate way to design such a trial?

A: There are a few different approaches. The first may be to figure out how to dose these CAR T cells. So, instead of giving a lot of them at once, one could give smaller amounts spread out over a shorter period of time. Also, building in a ‘kill switch’ can be another approach.

 

Q: In broad terms, what are the potential implications if CAR T-cell therapy is proven to be effective for colorectal cancer specifically, and other solid tumors in general?

A: There are very few effective therapies for advanced-stage colorectal cancer. If we can translate the positive effect observed with leukemias to the advanced-stage colon cancer area, this can have a significant impact on these patients. Approximately 50,000 people die of colon cancer annually in the United States. We could potentially make a dramatic impact here. – by Jennifer Southall

 

Reference:

Magee MS, et al. Cancer Immunol Res. 2018;doi:10.1158/2326-6066.CIR-16-0362.

For more information:

Adam Snook, PhD, can be reached at Thomas Jefferson University and Jefferson Health, 1020 Locust St., Suite 368, Philadelphia, PA 19107; email: adam.snook@jefferson.edu

Disclosure: Snook reports no relevant financial disclosures.

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