T-cell receptor gene therapy could effectively target leukemia relapse

Marie Bleakley 

Researchers at Fred Hutchinson Cancer Research Center and University of Washington developed a novel way to genetically engineer T cells for the treatment and prevention of leukemia relapse.

About one-third of patients with acute leukemia who undergo stem cell transplantation will relapse. Average survival for these patients after relapse is about 4 months.

The HA-1 T-cell receptor immunotherapy clinical trial will enroll adults and children with acute myeloid leukemia, T-lineage acute lymphoblastic leukemia or B-lineage acute lymphoblastic leukemia who develop recurrent leukemia after hematopoietic stem cell transplantation.

“New therapies are desperately needed to prevent and treat relapse of leukemia in patients who have undergone hematopoietic stem cell transplantation,” Marie Bleakley, MD, PhD, MMSc, program director for transplantation in pediatric leukemia at Fred Hutchinson Cancer Research Center, as well as attending physician at Seattle Cancer Care Alliance and Seattle Children’s Hospital, said in a press release.

In a preliminary paper published in Blood, Bleakley and colleagues sought to exploit a specific minor histocompatibility antigen located on the surface of leukemia cells in certain patients with acute leukemia.

Minor histocompatibility antigens were expressed predominantly on blood-forming cells; thus, targeting the antigens potentially could provide a potent and selective antileukemia treatment with little risk to otherwise healthy cells, according to the researchers.

“T-cell receptors isolated from minor H antigen-specific T cells represent an untapped resource for developing targeted T-cell immunotherapy to manage leukemia relapse,” Bleakley said. “The construct used in this study could serve as a prototype for others targeting similar antigens.”

HemOnc Today spoke with Bleakley about how the approach works, why she believes it will be effective and safe, and whether there is reason to believe this could be beneficial for malignancies beyond leukemia or — at the very least — lay the groundwork for similar therapeutic approaches that could have broader implications.

 

Question: Can you describe this approach and how it works?

Answer: The new T-cell immunotherapy will be given to patients with acute leukemia after they have received stem cell transplantation — either marrow or peripheral blood stem cell transplantation — if and when they begin to relapse. The immunotherapy involves donor T cells that are collected and genetically modified to express a receptor that recognizes a protein fragment that is present on the patient’s leukemia, but not on the normal donor or blood or marrow cells. The immunotherapy is given as a single IV infusion. The T cells with receptor are able to migrate to the site of the leukemia in the patient’s body and effectively kill the leukemia cells.

 

Q: Why do you believe this approach will be effective and safe?

A : First, we have performed extensive lab studies to assess this particular form of immunotherapy. Second, what we are doing is actually amplifying the response that occurs in some patients during the routine process of transplantation. These lower level of responses that occur in some patients have been studied and observed to be safe.

Q: How does it differ from chimeric antigen receptor (CAR) T-cell therapy?

A: We are using a natural T-cell receptor. In our bodies, we have T cells that are able to respond to protein fragments that mark infected cells and cancer cells. Each of those T cells has a receptor that feeds the diseased cells. We can isolate those T cells and isolate the receptors from them, and we will use a viral approach to transfer them to the donor T cells. CAR T-cell therapy is a synthetic receptor, whereas T-cell receptor therapy is a naturally occurring receptor that moves from one T cell to other T cells.

 

Q: Is there reason to believe this could be beneficial in other malignancies beyond leukemia ?

A: This particular T-cell receptor T-cell therapy could very easily work in lymphomas, as well as in leukemia. There is the possibility that it could work in other solid tumors, but more work needs to be done there. In addition, this is a new form T-cell receptor therapy in that it is designed to work in both CD4 and CD8 T-cells. What we learn from this particular trial about the use of CD4 T cells will be important for the building of T-cell immunotherapy trials for a range of cancers.

 

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

A: We would like other oncologists in the community to be aware of the HA-1 TCR T-cell immunotherapy clinical trial as an option for patients with AML, T-lineage acute lymphoblastic leukemia or B-lineage acute lymphoblastic leukemia who develop recurrent leukemia after allogeneic transplantation. Very-high-risk patients who need to undergo transplantation with active disease can be referred to the trial for screening and monitoring, and could then be treated with the HA-1 T-cell receptor T cells at the first signs of recurrent disease after transplantation. For more information about the trial, go to clinicaltrials.gov/ct2/show/NCT03326921. – by Jennifer Southall

 

Reference:

Dossa RG, et al. Blood. 2017;doi:10.1182/blood-2017-07-791608.

 

For more information:

Marie Bleakley, MD, can be reached at Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Mail Stop J5-300, Seattle, WA 98109; email: mbleakle@fredhutch.org.

 

Disclosure: Bleakley reports no relevant financial disclosures.

Marie Bleakley 

Researchers at Fred Hutchinson Cancer Research Center and University of Washington developed a novel way to genetically engineer T cells for the treatment and prevention of leukemia relapse.

About one-third of patients with acute leukemia who undergo stem cell transplantation will relapse. Average survival for these patients after relapse is about 4 months.

The HA-1 T-cell receptor immunotherapy clinical trial will enroll adults and children with acute myeloid leukemia, T-lineage acute lymphoblastic leukemia or B-lineage acute lymphoblastic leukemia who develop recurrent leukemia after hematopoietic stem cell transplantation.

“New therapies are desperately needed to prevent and treat relapse of leukemia in patients who have undergone hematopoietic stem cell transplantation,” Marie Bleakley, MD, PhD, MMSc, program director for transplantation in pediatric leukemia at Fred Hutchinson Cancer Research Center, as well as attending physician at Seattle Cancer Care Alliance and Seattle Children’s Hospital, said in a press release.

In a preliminary paper published in Blood, Bleakley and colleagues sought to exploit a specific minor histocompatibility antigen located on the surface of leukemia cells in certain patients with acute leukemia.

Minor histocompatibility antigens were expressed predominantly on blood-forming cells; thus, targeting the antigens potentially could provide a potent and selective antileukemia treatment with little risk to otherwise healthy cells, according to the researchers.

“T-cell receptors isolated from minor H antigen-specific T cells represent an untapped resource for developing targeted T-cell immunotherapy to manage leukemia relapse,” Bleakley said. “The construct used in this study could serve as a prototype for others targeting similar antigens.”

HemOnc Today spoke with Bleakley about how the approach works, why she believes it will be effective and safe, and whether there is reason to believe this could be beneficial for malignancies beyond leukemia or — at the very least — lay the groundwork for similar therapeutic approaches that could have broader implications.

 

Question: Can you describe this approach and how it works?

Answer: The new T-cell immunotherapy will be given to patients with acute leukemia after they have received stem cell transplantation — either marrow or peripheral blood stem cell transplantation — if and when they begin to relapse. The immunotherapy involves donor T cells that are collected and genetically modified to express a receptor that recognizes a protein fragment that is present on the patient’s leukemia, but not on the normal donor or blood or marrow cells. The immunotherapy is given as a single IV infusion. The T cells with receptor are able to migrate to the site of the leukemia in the patient’s body and effectively kill the leukemia cells.

 

Q: Why do you believe this approach will be effective and safe?

A : First, we have performed extensive lab studies to assess this particular form of immunotherapy. Second, what we are doing is actually amplifying the response that occurs in some patients during the routine process of transplantation. These lower level of responses that occur in some patients have been studied and observed to be safe.

 

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Q: How does it differ from chimeric antigen receptor (CAR) T-cell therapy?

A: We are using a natural T-cell receptor. In our bodies, we have T cells that are able to respond to protein fragments that mark infected cells and cancer cells. Each of those T cells has a receptor that feeds the diseased cells. We can isolate those T cells and isolate the receptors from them, and we will use a viral approach to transfer them to the donor T cells. CAR T-cell therapy is a synthetic receptor, whereas T-cell receptor therapy is a naturally occurring receptor that moves from one T cell to other T cells.

 

Q: Is there reason to believe this could be beneficial in other malignancies beyond leukemia ?

A: This particular T-cell receptor T-cell therapy could very easily work in lymphomas, as well as in leukemia. There is the possibility that it could work in other solid tumors, but more work needs to be done there. In addition, this is a new form T-cell receptor therapy in that it is designed to work in both CD4 and CD8 T-cells. What we learn from this particular trial about the use of CD4 T cells will be important for the building of T-cell immunotherapy trials for a range of cancers.

 

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

A: We would like other oncologists in the community to be aware of the HA-1 TCR T-cell immunotherapy clinical trial as an option for patients with AML, T-lineage acute lymphoblastic leukemia or B-lineage acute lymphoblastic leukemia who develop recurrent leukemia after allogeneic transplantation. Very-high-risk patients who need to undergo transplantation with active disease can be referred to the trial for screening and monitoring, and could then be treated with the HA-1 T-cell receptor T cells at the first signs of recurrent disease after transplantation. For more information about the trial, go to clinicaltrials.gov/ct2/show/NCT03326921. – by Jennifer Southall

 

Reference:

Dossa RG, et al. Blood. 2017;doi:10.1182/blood-2017-07-791608.

 

For more information:

Marie Bleakley, MD, can be reached at Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Mail Stop J5-300, Seattle, WA 98109; email: mbleakle@fredhutch.org.

 

Disclosure: Bleakley reports no relevant financial disclosures.

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