Chimeric antigen receptor T cells targeting the tyrosine kinase receptor ROR1 can be transferred into patients safely and the cells expand in vivo.
Jennifer Specht, MD
Chimeric antigen receptor (CAR) T cells targeting the tyrosine kinase receptor ROR1 can be transferred into patients safely and the cells expand in vivo, according to first in-human study of CAR T cells in patients with solid tumors.
Although post-treatment tumor biopsy revealed an influx of T cells and suggested ROR1 CAR T cells trafficked to tumor sites, CAR T cells developed an activated-exhausted phenotype at day 14 post infusion, according to findings from the ongoing phase I study presented at the 2018 San Antonio Breast Cancer Symposium.
The data presented by Jennifer Specht, MD, were from 7 patients with ROR1-expressing triple negative breast cancer (TNBC) who are being treated at up to 5 dose levels of CAR T cells. ROR1 is an orphan tyrosine kinase orphan receptor that is expressed in TNBC and non—small cell lung cancers. Enrolled patients had adequate organ function and performance status, measurable disease, and ROR1 expression in their tumors >20% by immunohistochemistry.
Embryonic expression of ROR1 is high but expression in adult cells is limited. High levels of ROR1 expression in breast cancer are associated with poor prognosis and may contribute to resistance to conventional therapies, said Specht, an associate professor in the Medical Oncology Division of the University of Washington, Seattle.
“These are early days. This study continues to enroll. We’ve treated 7 patients to date, and we’re now treating at dose level 3 of the CAR T cells, up to 3.3 x 106 transfused T-cells/kg,” she said. “These were heavily pretreated patients. We have seen no significant dose-limiting toxicities to date. We have seen 1 patient recently who developed grade-3 cytokine release syndrome [CRS] that quickly responded to dexamethasone and tocilizumab. We are able to detect expansion of the CAR-T cells in most patients but not at particularly high levels, and we have not seen any significant on-target, off-tumor toxicities related to ROR1 expression.” There have been no instances of severe neurotoxicity, severe CRS, or tumor lysis syndrome.
All patients treated (age range, 27-67 years) had at least 3 lines of prior metastatic therapies. Three patients were treated with as many as 9 prior lines, and 1 received 11. Dose levels were as follows: up to 1 x 105 cells/kg (dose level 0), up to 3.3 x 105 (level 1), up to 1 x 106 (level 2), up to 3.3 x 106 (level 3), and up to 1 x 107 (level 4). CAR-T cells are infused following lymphodepletion with cyclophosphamide-containing regimens using a continual reassessment method for dose escalation.
The CAR-T construct being used is a second-generation product engineered with lentiviral vector encoding ROR1 scFv/4-1BB/CD3ζ and a truncated EGFR molecule to permit elimination of ROR1 CAR-T cells in case of toxicity. The CAR-T cell product is formulated in a 1:1 ratio of CD4+ and CD8+ CAR-T cells.
Imaging assessments by RECIST 1.1 are performed at day 28 to 90, then at 6 and 12 months, and then every 6 months as clinically indicated to estimate efficacy.
“It’s [too] early to say much about responses, but clinically we have seen some patients with heavily pretreated TNBC who have prolonged stable disease [1 at 15 weeks and 1 at 19 weeks], with no subsequent therapy beyond the CAR-T cells,” Specht said. One patient with stable disease after the first infusion has had a partial response lasting 14 weeks after the second infusion.
“We have lots of things to work on in terms of potential barriers to this therapy,” Specht said. “The T-cells that persist do seem to suggest that there’s an exhausted phenotype of those T-cells, so work needs to be done to overcome that exhaustion. We also are trying to understand better how the T cells are trafficking to tumor cells. It’s very different from hematologic malignancies where your cells of interest are easily accessible.”
Specht JM, Lee SM, Turtle C, et al. A phase I study of adoptive immunotherapy for ROR1+ advanced triple negative breast cancer (TNBC) with defined subsets of autologous T cells expressing a ROR1-specific chimeric antigen receptor (ROR1-CAR). Presented at: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, Texas. P2-09-13.