Novel approach may prolong remission after T-cell immunotherapy for leukemia, lymphoma

Researchers at Seattle Children’s Hospital have launched a first-in-human trial to investigate whether infusions of T-cell antigen–presenting cells prolong the persistence of chimeric antigen receptor T-cell immunotherapy among children with relapsed or refractory acute lymphoblastic leukemia or lymphoma.

A previous phase 1/phase 2 trial showed chimeric antigen receptor (CAR) T-cell immunotherapy induced complete remission in 93% of patients with relapsed or refractory ALL.

Colleen E. Annesley

However, nearly half of all children relapsed.

Colleen E. Annesley, MD, oncologist at Seattle Children’s Hospital, and colleagues will conduct the PLAT-03 trial to evaluate the feasibility and safety of antigen–presenting cells designed to reactivate the CAR T-cell response.

“We are engineering the T-cell antigen–presenting cells to express CD19, which is what the CAR recognizes on the cancer-fighting CAR T-cells,” Annesley told HemOnc Today. “We will give the T-cell antigen–presenting cells to patients after they have received their CAR T-cell infusion and are in remission. In a way, the T-cell antigen–presenting cells present the CD19 to the CAR T cells for them to recognize, which causes the CAR T cells to reactivate and continue fighting any residual cancer cells. The T-cell antigen–presenting cells almost act as a booster shot.”

HemOnc Today spoke with Annesley about the rationale for this study, when she anticipates results and why new treatments are needed to prevent relapses in this patient population.

Question: What prompted this research?

Answer: We are one of few institutions that have designed a CAR T-cell trial for pediatric patients with relapsed or refractory ALL or lymphoma. At Seattle Children’s, we have seen a 93% remission rate with this therapy, which is outstanding considering that many of these patients were refractory to conventional chemotherapy treatments. However, we also see about a 50% chance for relapse nearly 1 year out from therapy. Even though CAR T-cell therapy has been remarkably effective at getting patients in remission, it is not perfect. We know we have more work to do.

Q: Why is relapse so common in this patient population?

A: There are several reasons why these children relapse. We believe one reason is that they have lost persistence of their CAR T cells too early. The CAR T cells worked initially, and then they became exhausted or were rejected. This is where the concept for our new trial, PLAT-03, was born. The idea is that, if we can reactivate the CAR T cells in the body, this will cause the CAR T cells to persist longer. This will have a protective effect and decrease the risk for relapse.

Q: Can you describe the trial?

A: At this point, we are only enrolling patients on PLAT-03 who first enroll on PLAT-02, our CD19 CAR T-cell trial. This way, we can use the patient’s original stored T-cell collection to manufacture the new booster cells, or T-cell antigen–presenting cells. We hope to enroll up to 30 patients between the ages of 1 year and 26 years. Patients will be eligible if they are at risk for losing their CAR T cells early, or if they already lost their CAR T cells early. Patients who already lost their CAR T cells will receive a second infusion of CAR T cells, followed by the booster T-cell antigen–presenting cells infusion. Patients may receive up to six total monthly doses of T-cell antigen–presenting cells.

Q: Are there any insights on safety/efficacy at this point?

A: Not at this point. Because this is a first-in-human clinical trial, there is no previous safety or efficacy data. The first patient enrolled on our trial will be the first person to receive these cells. Because of this, we will track safety and toxicity closely. We also will look for changes in the number or activity of CAR T cells after patients receive a dose of T-cell antigen–presenting cells. We are very excited to see how these work in the first patients.

Q: When do you anticipate results?

A: We speculate that the PLAT-03 trial will take 2 to 3 years to complete. We hope, after the first three to five patients are enrolled, that we will have an early idea as to how the T-cell antigen–presenting cells are tolerated and how they are working.

Q: After this trial is complete, what is next for research?

A: This trial is one of several at Seattle Children’s Hospital that aim to further improve upon the efficacy of T-cell immunotherapy in leukemia. However, if the booster infusions of T-cell antigen–presenting cells are well tolerated and effective in PLAT-03, one might imagine expanding this concept to CAR T-cell immunotherapy for other tumor types.

Q: Is there anything else that you feel is important to mention?

A: We are very enthusiastic about this trial. It is an indescribable feeling to go into a patient’s room and tell them that, after they have failed multiple treatments, CAR T-cell therapy has worked for them and they are now in remission. They are elated, we are elated, and it never gets old. On the other hand, it is disheartening when a subset of these patients go through this treatment and their disease eventually returns. Immunotherapy is a growing and developing field. We are building on new knowledge gained in real time, with the goal of providing a long-term cure for all of these patients. – by Jennifer Southall

Reference:

Gardner RA, et al. Blood. 2017;doi:10.1182/blood-2017-02-769208.

For more information:

Colleen E. Annesley, MD, can be reached at Seattle Children’s Hospital, 4800 Sand Point Way NE, M/S MB8.501, Seattle, WA 98105; email: colleen.annesley@seattlechildrens.org.

Disclosure: Annesley reports no relevant financial disclosures.

Researchers at Seattle Children’s Hospital have launched a first-in-human trial to investigate whether infusions of T-cell antigen–presenting cells prolong the persistence of chimeric antigen receptor T-cell immunotherapy among children with relapsed or refractory acute lymphoblastic leukemia or lymphoma.

A previous phase 1/phase 2 trial showed chimeric antigen receptor (CAR) T-cell immunotherapy induced complete remission in 93% of patients with relapsed or refractory ALL.

Colleen E. Annesley

However, nearly half of all children relapsed.

Colleen E. Annesley, MD, oncologist at Seattle Children’s Hospital, and colleagues will conduct the PLAT-03 trial to evaluate the feasibility and safety of antigen–presenting cells designed to reactivate the CAR T-cell response.

“We are engineering the T-cell antigen–presenting cells to express CD19, which is what the CAR recognizes on the cancer-fighting CAR T-cells,” Annesley told HemOnc Today. “We will give the T-cell antigen–presenting cells to patients after they have received their CAR T-cell infusion and are in remission. In a way, the T-cell antigen–presenting cells present the CD19 to the CAR T cells for them to recognize, which causes the CAR T cells to reactivate and continue fighting any residual cancer cells. The T-cell antigen–presenting cells almost act as a booster shot.”

HemOnc Today spoke with Annesley about the rationale for this study, when she anticipates results and why new treatments are needed to prevent relapses in this patient population.

Question: What prompted this research?

Answer: We are one of few institutions that have designed a CAR T-cell trial for pediatric patients with relapsed or refractory ALL or lymphoma. At Seattle Children’s, we have seen a 93% remission rate with this therapy, which is outstanding considering that many of these patients were refractory to conventional chemotherapy treatments. However, we also see about a 50% chance for relapse nearly 1 year out from therapy. Even though CAR T-cell therapy has been remarkably effective at getting patients in remission, it is not perfect. We know we have more work to do.

Q: Why is relapse so common in this patient population?

A: There are several reasons why these children relapse. We believe one reason is that they have lost persistence of their CAR T cells too early. The CAR T cells worked initially, and then they became exhausted or were rejected. This is where the concept for our new trial, PLAT-03, was born. The idea is that, if we can reactivate the CAR T cells in the body, this will cause the CAR T cells to persist longer. This will have a protective effect and decrease the risk for relapse.

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Q: Can you describe the trial?

A: At this point, we are only enrolling patients on PLAT-03 who first enroll on PLAT-02, our CD19 CAR T-cell trial. This way, we can use the patient’s original stored T-cell collection to manufacture the new booster cells, or T-cell antigen–presenting cells. We hope to enroll up to 30 patients between the ages of 1 year and 26 years. Patients will be eligible if they are at risk for losing their CAR T cells early, or if they already lost their CAR T cells early. Patients who already lost their CAR T cells will receive a second infusion of CAR T cells, followed by the booster T-cell antigen–presenting cells infusion. Patients may receive up to six total monthly doses of T-cell antigen–presenting cells.

Q: Are there any insights on safety/efficacy at this point?

A: Not at this point. Because this is a first-in-human clinical trial, there is no previous safety or efficacy data. The first patient enrolled on our trial will be the first person to receive these cells. Because of this, we will track safety and toxicity closely. We also will look for changes in the number or activity of CAR T cells after patients receive a dose of T-cell antigen–presenting cells. We are very excited to see how these work in the first patients.

Q: When do you anticipate results?

A: We speculate that the PLAT-03 trial will take 2 to 3 years to complete. We hope, after the first three to five patients are enrolled, that we will have an early idea as to how the T-cell antigen–presenting cells are tolerated and how they are working.

Q: After this trial is complete, what is next for research?

A: This trial is one of several at Seattle Children’s Hospital that aim to further improve upon the efficacy of T-cell immunotherapy in leukemia. However, if the booster infusions of T-cell antigen–presenting cells are well tolerated and effective in PLAT-03, one might imagine expanding this concept to CAR T-cell immunotherapy for other tumor types.

Q: Is there anything else that you feel is important to mention?

A: We are very enthusiastic about this trial. It is an indescribable feeling to go into a patient’s room and tell them that, after they have failed multiple treatments, CAR T-cell therapy has worked for them and they are now in remission. They are elated, we are elated, and it never gets old. On the other hand, it is disheartening when a subset of these patients go through this treatment and their disease eventually returns. Immunotherapy is a growing and developing field. We are building on new knowledge gained in real time, with the goal of providing a long-term cure for all of these patients. – by Jennifer Southall

Reference:

Gardner RA, et al. Blood. 2017;doi:10.1182/blood-2017-02-769208.

For more information:

Colleen E. Annesley, MD, can be reached at Seattle Children’s Hospital, 4800 Sand Point Way NE, M/S MB8.501, Seattle, WA 98105; email: colleen.annesley@seattlechildrens.org.

Disclosure: Annesley reports no relevant financial disclosures.