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University of Pennsylvania
NEW YORK—The 5-year follow-up of the phase 1 trial of CTL019 in relapsed or refractory chronic lymphoblastic leukemia (CLL) is allowing investigators to define more clearly who will respond to chimeric antigen receptor (CAR) T cells directed against CD19.
One thing investigators have determined is that persistence of the CARs is essential for long-term responses.
In the first 2 patients who achieved a complete remission (CR), CAR T cells persisted for more than 4 years. In addition, no patient in CR has relapsed to date.
Of the 14 patients enrolled in the trial, 4 (28%) achieved a CR, 4 (28%) achieved a partial response, and 6 (43%) had no response, for an overall response rate of 57%.
These results were recently published in Science Translational Medicine.
Carl June, MD, of the University of Pennsylvania in Philadelphia, shared some insights into the research with attendees at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.
Dr June explained that CTL019 is a CD19-directed single chain variable fragment with a 4-1BB signaling module that transduces T cells with a lentiviral vector. The technology was developed at the University of Pennsylvania and subsequently licensed to Novartis.
In the phase 1 trial of CTL019 in CLL, patients who achieved complete remission have very high levels of CARs—100% of the circulating T cells—but the non-responders don’t. The CARs engrafted in non-responders but did not proliferate.
“So the biomarker correlate of success is persistence and proliferation, in CLL at least,” Dr June said.
The investigators performed IGH next-generation sequencing and found no detectable CLL clones in the complete responders, including 1 patient at 3.5 years and another at 4 years post-infusion.
“There was no clinically evident disease in these patients,” Dr June said, “and so the responses are durable.”
The team also believes that at least a subset of the cells remains functional because the patients still had B-cell aplasia.
The investigators have not observed a CD19 loss in any CLL patient who responded.
“Patients who have gone into remission stay in remission,” Dr June added.
Kinetics of delayed CR
Dr June discussed in detail Patient 10, whose response was somewhat different from the other complete responders. Patient 10 achieved a CR, but the response was delayed. It took 51 days after infusion, compared to about 10 days in the other complete responders.
Patient 10 was initially scored as a failure at the 28-day evaluation. Eventually, he had marked improvement, and, by a year, he was in CR.
He required hospitalization for tumor lysis syndrome and treatment with tocilizumab for cytokine release syndrome.
Patient 10 had a single cell that investigators surmise could have been responsible for the tumor elimination.
“In fact, on day 28, when he still had tumor, his CARs were polyclonal,” Dr June said. “So we stained and isolated his CARs by sorting, and, at time of tumor elimination, he had descendants of 1 CAR.”
Nevertheless, Patient 10’s response is durable. He is now 81 years old and remains engrafted with CAR19 cells.
Investigators hypothesize that the kinetics and CAR proliferation were so different in Patient 10 because Tet2 was disrupted by the integration of the CAR into the intronic region.
“What we don’t know is whether Tet2 was a passenger or a driver here,” Dr June observed. “Did it actually aid the function of the CAR cells or was it just a marker?”
He noted that Tet2 has been shown in acute myeloid leukemia to increase stem cell renewal, “and it may well have done that in this patient.” 
Photo courtesy of the
University of Pennsylvania
NEW YORK—The 5-year follow-up of the phase 1 trial of CTL019 in relapsed or refractory chronic lymphoblastic leukemia (CLL) is allowing investigators to define more clearly who will respond to chimeric antigen receptor (CAR) T cells directed against CD19.
One thing investigators have determined is that persistence of the CARs is essential for long-term responses.
In the first 2 patients who achieved a complete remission (CR), CAR T cells persisted for more than 4 years. In addition, no patient in CR has relapsed to date.
Of the 14 patients enrolled in the trial, 4 (28%) achieved a CR, 4 (28%) achieved a partial response, and 6 (43%) had no response, for an overall response rate of 57%.
These results were recently published in Science Translational Medicine.
Carl June, MD, of the University of Pennsylvania in Philadelphia, shared some insights into the research with attendees at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.
Dr June explained that CTL019 is a CD19-directed single chain variable fragment with a 4-1BB signaling module that transduces T cells with a lentiviral vector. The technology was developed at the University of Pennsylvania and subsequently licensed to Novartis.
In the phase 1 trial of CTL019 in CLL, patients who achieved complete remission have very high levels of CARs—100% of the circulating T cells—but the non-responders don’t. The CARs engrafted in non-responders but did not proliferate.
“So the biomarker correlate of success is persistence and proliferation, in CLL at least,” Dr June said.
The investigators performed IGH next-generation sequencing and found no detectable CLL clones in the complete responders, including 1 patient at 3.5 years and another at 4 years post-infusion.
“There was no clinically evident disease in these patients,” Dr June said, “and so the responses are durable.”
The team also believes that at least a subset of the cells remains functional because the patients still had B-cell aplasia.
The investigators have not observed a CD19 loss in any CLL patient who responded.
“Patients who have gone into remission stay in remission,” Dr June added.
Kinetics of delayed CR
Dr June discussed in detail Patient 10, whose response was somewhat different from the other complete responders. Patient 10 achieved a CR, but the response was delayed. It took 51 days after infusion, compared to about 10 days in the other complete responders.
Patient 10 was initially scored as a failure at the 28-day evaluation. Eventually, he had marked improvement, and, by a year, he was in CR.
He required hospitalization for tumor lysis syndrome and treatment with tocilizumab for cytokine release syndrome.
Patient 10 had a single cell that investigators surmise could have been responsible for the tumor elimination.
“In fact, on day 28, when he still had tumor, his CARs were polyclonal,” Dr June said. “So we stained and isolated his CARs by sorting, and, at time of tumor elimination, he had descendants of 1 CAR.”
Nevertheless, Patient 10’s response is durable. He is now 81 years old and remains engrafted with CAR19 cells.
Investigators hypothesize that the kinetics and CAR proliferation were so different in Patient 10 because Tet2 was disrupted by the integration of the CAR into the intronic region.
“What we don’t know is whether Tet2 was a passenger or a driver here,” Dr June observed. “Did it actually aid the function of the CAR cells or was it just a marker?”
He noted that Tet2 has been shown in acute myeloid leukemia to increase stem cell renewal, “and it may well have done that in this patient.”
Photo courtesy of the
University of Pennsylvania
NEW YORK—The 5-year follow-up of the phase 1 trial of CTL019 in relapsed or refractory chronic lymphoblastic leukemia (CLL) is allowing investigators to define more clearly who will respond to chimeric antigen receptor (CAR) T cells directed against CD19.
One thing investigators have determined is that persistence of the CARs is essential for long-term responses.
In the first 2 patients who achieved a complete remission (CR), CAR T cells persisted for more than 4 years. In addition, no patient in CR has relapsed to date.
Of the 14 patients enrolled in the trial, 4 (28%) achieved a CR, 4 (28%) achieved a partial response, and 6 (43%) had no response, for an overall response rate of 57%.
These results were recently published in Science Translational Medicine.
Carl June, MD, of the University of Pennsylvania in Philadelphia, shared some insights into the research with attendees at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.
Dr June explained that CTL019 is a CD19-directed single chain variable fragment with a 4-1BB signaling module that transduces T cells with a lentiviral vector. The technology was developed at the University of Pennsylvania and subsequently licensed to Novartis.
In the phase 1 trial of CTL019 in CLL, patients who achieved complete remission have very high levels of CARs—100% of the circulating T cells—but the non-responders don’t. The CARs engrafted in non-responders but did not proliferate.
“So the biomarker correlate of success is persistence and proliferation, in CLL at least,” Dr June said.
The investigators performed IGH next-generation sequencing and found no detectable CLL clones in the complete responders, including 1 patient at 3.5 years and another at 4 years post-infusion.
“There was no clinically evident disease in these patients,” Dr June said, “and so the responses are durable.”
The team also believes that at least a subset of the cells remains functional because the patients still had B-cell aplasia.
The investigators have not observed a CD19 loss in any CLL patient who responded.
“Patients who have gone into remission stay in remission,” Dr June added.
Kinetics of delayed CR
Dr June discussed in detail Patient 10, whose response was somewhat different from the other complete responders. Patient 10 achieved a CR, but the response was delayed. It took 51 days after infusion, compared to about 10 days in the other complete responders.
Patient 10 was initially scored as a failure at the 28-day evaluation. Eventually, he had marked improvement, and, by a year, he was in CR.
He required hospitalization for tumor lysis syndrome and treatment with tocilizumab for cytokine release syndrome.
Patient 10 had a single cell that investigators surmise could have been responsible for the tumor elimination.
“In fact, on day 28, when he still had tumor, his CARs were polyclonal,” Dr June said. “So we stained and isolated his CARs by sorting, and, at time of tumor elimination, he had descendants of 1 CAR.”
Nevertheless, Patient 10’s response is durable. He is now 81 years old and remains engrafted with CAR19 cells.
Investigators hypothesize that the kinetics and CAR proliferation were so different in Patient 10 because Tet2 was disrupted by the integration of the CAR into the intronic region.
“What we don’t know is whether Tet2 was a passenger or a driver here,” Dr June observed. “Did it actually aid the function of the CAR cells or was it just a marker?”
He noted that Tet2 has been shown in acute myeloid leukemia to increase stem cell renewal, “and it may well have done that in this patient.”