Purpose:

The receptor tyrosine kinase–like orphan receptor 1 (ROR1) is expressed in hematopoietic and epithelial cancers but has limited expression on normal adult tissues. This phase I study evaluated the safety of targeting ROR1 with autologous T lymphocytes engineered to express a ROR1 chimeric antigen receptor (CAR). Secondary objectives evaluated the persistence, trafficking, and antitumor activity of CAR-T cells.

Patients and Methods:

Twenty-one patients with ROR1+ tumors received CAR-T cells at one of four dose levels: 3.3 × 105, 1 × 106, 3.3 × 106, and 1 × 107 cells/kg body weight, administered after lymphodepletion with cyclophosphamide/fludarabine or oxaliplatin/cyclophosphamide. Cohort A included patients with chronic lymphocytic leukemia (CLL, n = 3); cohort B included patients with triple-negative breast cancer (TNBC, n = 10) or non–small cell lung cancer (NSCLC, n = 8). A second infusion was administered to one patient in cohort A with residual CLL in the marrow and three patients in cohort B with stable disease after first infusion.

Results:

Treatment was well tolerated, apart from one dose-limiting toxicity at dose level 4 in a patient with advanced NSCLC. Two of the three (67%) patients with CLL showed robust CAR-T–cell expansion and a rapid antitumor response. In patients with NSCLC and TNBC, CAR-T cells expanded to variable levels and infiltrated tumors poorly and 1 of 18 patients (5.5%) achieved partial response by RECIST 1.1.

Conclusions:

ROR1 CAR-T cells were well tolerated in most patients. Antitumor activity was observed in CLL but was limited in TNBC and NSCLC. Immunogenicity of the CAR and lack of sustained tumor infiltration were identified as limitations.

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©2024 The Authors; Published by the American Association for Cancer Research
2024
American Association for Cancer Research
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Supplementary data

Supplementary Table 2

Supplementary Table 2: Patient and tumor characteristics.

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Supplementary Table 3

Supplementary Table 3: Summary of adverse events Cohorts A and B, NCI CTCAE grading.

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Supplementary Data 1

Supplementary Data 1: Study Protocol.

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Supplementary Figure 1

Supplementary Figure 1: Strobe Flow Diagram.

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Supplementary Figure 2

Supplementary Figure 2: Toxicity Assessment.

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Supplementary Figure 3

Supplementary Figure 3: Lymphodepletion and CAR T cell expansion.

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Supplementary Figure 4

Supplementary Figure 4: Flow cytometric analysis of T cell phenotypes in apheresis, infusion products and EGFRt + CAR T cells at peak of expansion.

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Supplementary Table 1

Supplementary Table 1: Representativeness of Study Participants.

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