User login
, according to results of an ongoing phase 1 trial.
In one of three patients treated thus far, the CAR NKT cells induced an objective response with regression of a metastatic bone lesion.
Andras Heczey, MD, of Baylor College of Medicine, Houston, and colleagues reported outcomes for the first three patients in Nature Medicine.
The three boys – two 12-year-olds and one 6-year-old – had relapsed/refractory neuroblastoma.
NKT cells were collected from the patients, then genetically engineered to express a CAR to recognize the GD2-ganglioside expressed in neuroblastomas and also to express interleukin-15, which supports NKT cell survival. The cells were expanded and reinfused back into the patients.
The initial results suggest that CAR NKT cells can be used safely to treat neuroblastomas and perhaps other solid tumors, investigators said.
‘A significant advance’ if confirmed
Treating solid tumors with CAR T cells has been a challenge, in part because of inefficient trafficking into tumors.
However, NKT cells naturally migrate to tumors in response to tumor-derived chemokines, Dr. Heczey and colleagues noted. NKT cells kill macrophages associated with tumor growth and promote NK- and T-cell–mediated antitumor responses.
“We decided to leverage this intrinsic property of NKTs and to arm them with an additional bullet – the so-called CAR – to further potentiate their capacity to destroy the tumor,” investigator Gianpietro Dotti, MD, of the University of North Carolina Lindberger Comprehensive Cancer Center in Chapel Hill, said in a press release.
Overall, the “results are very encouraging and, if confirmed in a larger cohort of patients, present a significant advance in the cell therapy field for solid tumors,” said CAR-T researcher Stephen Gottschalk, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn., when asked for comment.
Treatment, safety, and efficacy details
NKT cells are infrequent in human peripheral blood, so the investigators stimulated the NKT cells collected from patients with alpha-galactosylceramide–pulsed irradiated peripheral blood mononuclear cells.
The final products reached a mean NKT cell purity of 95%. The proportion of cells positive for the GD2-CAR ranged from 20% to 70% across the three patients.
After lymphodepletion with cyclophosphamide/fludarabine, the patients were infused with 3 × 106 CAR NKT cells/m2.
The cells were well tolerated, with no dose-limiting toxicities. There were grade 3/4 adverse events, but they occurred before CAR NKT-cell infusion and were thought to be related to lymphodepletion.
NKT-cell frequency and absolute numbers increased in the peripheral blood over baseline and remained elevated at the week 4 assessment.
Two patients had stable disease at 4 weeks, but one had a partial response and a change in Curie score from 2 to 1. The patient’s SPECT- and MIBG-merged scans “revealed a dramatic reduction in the size and MIBG uptake of a bone metastasis. The patient consequently received salvage therapy and achieved a complete response that lasted approximately 6 months,” the investigators noted.
The team found higher percentages of CAR NKT cells in primary tumor and metastatic bone marrow biopsies than in peripheral blood. A high percentage of CAR NKT cells from the tumor specimen, but only a small fraction from the bone metastasis, expressed the GD2-CAR.
This research was funded by Kuur Therapeutics, Alex’s Lemonade Stand Foundation for Childhood Cancer, the American Cancer Society, Cookies for Kids’ Cancer Foundation, and the Cancer Prevention and Research Institute of Texas. Dr. Heczey, Dr. Dotti, and two other researchers are coinventors on pending patent applications for NKT cells in cancer immunotherapy that have been licensed to Kuur Therapeutics for commercial development. Dr. Gottschalk has patent applications in the fields of T-cell and/or gene therapy for cancer. He has relationships with TESSA Therapeutics, Immatics, and Tidal.
SOURCE: Heczey A et al. Nat Med. 2020 Oct 12. doi: 10.1038/s41591-020-1074-2.
, according to results of an ongoing phase 1 trial.
In one of three patients treated thus far, the CAR NKT cells induced an objective response with regression of a metastatic bone lesion.
Andras Heczey, MD, of Baylor College of Medicine, Houston, and colleagues reported outcomes for the first three patients in Nature Medicine.
The three boys – two 12-year-olds and one 6-year-old – had relapsed/refractory neuroblastoma.
NKT cells were collected from the patients, then genetically engineered to express a CAR to recognize the GD2-ganglioside expressed in neuroblastomas and also to express interleukin-15, which supports NKT cell survival. The cells were expanded and reinfused back into the patients.
The initial results suggest that CAR NKT cells can be used safely to treat neuroblastomas and perhaps other solid tumors, investigators said.
‘A significant advance’ if confirmed
Treating solid tumors with CAR T cells has been a challenge, in part because of inefficient trafficking into tumors.
However, NKT cells naturally migrate to tumors in response to tumor-derived chemokines, Dr. Heczey and colleagues noted. NKT cells kill macrophages associated with tumor growth and promote NK- and T-cell–mediated antitumor responses.
“We decided to leverage this intrinsic property of NKTs and to arm them with an additional bullet – the so-called CAR – to further potentiate their capacity to destroy the tumor,” investigator Gianpietro Dotti, MD, of the University of North Carolina Lindberger Comprehensive Cancer Center in Chapel Hill, said in a press release.
Overall, the “results are very encouraging and, if confirmed in a larger cohort of patients, present a significant advance in the cell therapy field for solid tumors,” said CAR-T researcher Stephen Gottschalk, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn., when asked for comment.
Treatment, safety, and efficacy details
NKT cells are infrequent in human peripheral blood, so the investigators stimulated the NKT cells collected from patients with alpha-galactosylceramide–pulsed irradiated peripheral blood mononuclear cells.
The final products reached a mean NKT cell purity of 95%. The proportion of cells positive for the GD2-CAR ranged from 20% to 70% across the three patients.
After lymphodepletion with cyclophosphamide/fludarabine, the patients were infused with 3 × 106 CAR NKT cells/m2.
The cells were well tolerated, with no dose-limiting toxicities. There were grade 3/4 adverse events, but they occurred before CAR NKT-cell infusion and were thought to be related to lymphodepletion.
NKT-cell frequency and absolute numbers increased in the peripheral blood over baseline and remained elevated at the week 4 assessment.
Two patients had stable disease at 4 weeks, but one had a partial response and a change in Curie score from 2 to 1. The patient’s SPECT- and MIBG-merged scans “revealed a dramatic reduction in the size and MIBG uptake of a bone metastasis. The patient consequently received salvage therapy and achieved a complete response that lasted approximately 6 months,” the investigators noted.
The team found higher percentages of CAR NKT cells in primary tumor and metastatic bone marrow biopsies than in peripheral blood. A high percentage of CAR NKT cells from the tumor specimen, but only a small fraction from the bone metastasis, expressed the GD2-CAR.
This research was funded by Kuur Therapeutics, Alex’s Lemonade Stand Foundation for Childhood Cancer, the American Cancer Society, Cookies for Kids’ Cancer Foundation, and the Cancer Prevention and Research Institute of Texas. Dr. Heczey, Dr. Dotti, and two other researchers are coinventors on pending patent applications for NKT cells in cancer immunotherapy that have been licensed to Kuur Therapeutics for commercial development. Dr. Gottschalk has patent applications in the fields of T-cell and/or gene therapy for cancer. He has relationships with TESSA Therapeutics, Immatics, and Tidal.
SOURCE: Heczey A et al. Nat Med. 2020 Oct 12. doi: 10.1038/s41591-020-1074-2.
, according to results of an ongoing phase 1 trial.
In one of three patients treated thus far, the CAR NKT cells induced an objective response with regression of a metastatic bone lesion.
Andras Heczey, MD, of Baylor College of Medicine, Houston, and colleagues reported outcomes for the first three patients in Nature Medicine.
The three boys – two 12-year-olds and one 6-year-old – had relapsed/refractory neuroblastoma.
NKT cells were collected from the patients, then genetically engineered to express a CAR to recognize the GD2-ganglioside expressed in neuroblastomas and also to express interleukin-15, which supports NKT cell survival. The cells were expanded and reinfused back into the patients.
The initial results suggest that CAR NKT cells can be used safely to treat neuroblastomas and perhaps other solid tumors, investigators said.
‘A significant advance’ if confirmed
Treating solid tumors with CAR T cells has been a challenge, in part because of inefficient trafficking into tumors.
However, NKT cells naturally migrate to tumors in response to tumor-derived chemokines, Dr. Heczey and colleagues noted. NKT cells kill macrophages associated with tumor growth and promote NK- and T-cell–mediated antitumor responses.
“We decided to leverage this intrinsic property of NKTs and to arm them with an additional bullet – the so-called CAR – to further potentiate their capacity to destroy the tumor,” investigator Gianpietro Dotti, MD, of the University of North Carolina Lindberger Comprehensive Cancer Center in Chapel Hill, said in a press release.
Overall, the “results are very encouraging and, if confirmed in a larger cohort of patients, present a significant advance in the cell therapy field for solid tumors,” said CAR-T researcher Stephen Gottschalk, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn., when asked for comment.
Treatment, safety, and efficacy details
NKT cells are infrequent in human peripheral blood, so the investigators stimulated the NKT cells collected from patients with alpha-galactosylceramide–pulsed irradiated peripheral blood mononuclear cells.
The final products reached a mean NKT cell purity of 95%. The proportion of cells positive for the GD2-CAR ranged from 20% to 70% across the three patients.
After lymphodepletion with cyclophosphamide/fludarabine, the patients were infused with 3 × 106 CAR NKT cells/m2.
The cells were well tolerated, with no dose-limiting toxicities. There were grade 3/4 adverse events, but they occurred before CAR NKT-cell infusion and were thought to be related to lymphodepletion.
NKT-cell frequency and absolute numbers increased in the peripheral blood over baseline and remained elevated at the week 4 assessment.
Two patients had stable disease at 4 weeks, but one had a partial response and a change in Curie score from 2 to 1. The patient’s SPECT- and MIBG-merged scans “revealed a dramatic reduction in the size and MIBG uptake of a bone metastasis. The patient consequently received salvage therapy and achieved a complete response that lasted approximately 6 months,” the investigators noted.
The team found higher percentages of CAR NKT cells in primary tumor and metastatic bone marrow biopsies than in peripheral blood. A high percentage of CAR NKT cells from the tumor specimen, but only a small fraction from the bone metastasis, expressed the GD2-CAR.
This research was funded by Kuur Therapeutics, Alex’s Lemonade Stand Foundation for Childhood Cancer, the American Cancer Society, Cookies for Kids’ Cancer Foundation, and the Cancer Prevention and Research Institute of Texas. Dr. Heczey, Dr. Dotti, and two other researchers are coinventors on pending patent applications for NKT cells in cancer immunotherapy that have been licensed to Kuur Therapeutics for commercial development. Dr. Gottschalk has patent applications in the fields of T-cell and/or gene therapy for cancer. He has relationships with TESSA Therapeutics, Immatics, and Tidal.
SOURCE: Heczey A et al. Nat Med. 2020 Oct 12. doi: 10.1038/s41591-020-1074-2.
FROM NATURE MEDICINE