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Tumor Antigen and Receptor Densities Regulate Efficacy of a Chimeric Antigen Receptor Targeting Anaplastic Lymphoma Kinase.

ABSTRACT: We explored the utility of targeting anaplastic lymphoma kinase (ALK), a cell surface receptor overexpressed on pediatric solid tumors, using chimeric antigen receptor (CAR)-based immunotherapy. T cells expressing a CAR incorporating the single-chain variable fragment sequence of the ALK48 mAb linked to a 4-1BB-CD3? signaling domain lysed ALK-expressing tumor lines and produced interferon-gamma upon antigen stimulation but had limited anti-tumor efficacy in two xenograft models of human neuroblastoma. Further exploration demonstrated that cytokine production was highly dependent upon ALK target density and that target density of ALK on neuroblastoma cell lines was insufficient for maximal activation of CAR T cells. In addition, ALK CAR T cells demonstrated rapid and complete antigen-induced loss of receptor from the T cell surface via internalization. Using a model that simultaneously modulated antigen density and CAR expression, we demonstrated that CAR functionality is regulated by target antigen and CAR density and that low expression of either contributes to limited anti-tumor efficacy of the ALK CAR. These data suggest that stoichiometric relationships between CAR receptors and target antigens may significantly impact the anti-tumor efficacy of CAR T cells and that manipulation of these parameters could allow precise tuning of CAR T cell activity.

SUBMITTER: Walker AJ

PROVIDER: S-EPMC5589087 | biostudies-other | 2017 Sep

REPOSITORIES: biostudies-other

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Tumor Antigen and Receptor Densities Regulate Efficacy of a Chimeric Antigen Receptor Targeting Anaplastic Lymphoma Kinase.

Walker Alec J AJ Majzner Robbie G RG Zhang Ling L Wanhainen Kelsey K Long Adrienne H AH Nguyen Sang M SM Lopomo Paola P Vigny Marc M Fry Terry J TJ Orentas Rimas J RJ Mackall Crystal L CL

Molecular therapy : the journal of the American Society of Gene Therapy 20170701 9

We explored the utility of targeting anaplastic lymphoma kinase (ALK), a cell surface receptor overexpressed on pediatric solid tumors, using chimeric antigen receptor (CAR)-based immunotherapy. T cells expressing a CAR incorporating the single-chain variable fragment sequence of the ALK48 mAb linked to a 4-1BB-CD3ζ signaling domain lysed ALK-expressing tumor lines and produced interferon-gamma upon antigen stimulation but had limited anti-tumor efficacy in two xenograft models of human neurobla ...[more]

PMID: 28676342

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Project description:BackgroundA 4-1BB/CD3-ζ-costimulated CAR-T against CD20 (CAR-T20) was subjected to a systemic efficacy evaluation in a cell co-culture model, and NOD-SCID IL-2 receptor gamma null mice (short for NSG mice) were xenografted with human Burkitt's lymphoma Raji cells.MethodsCAR-T20 cells were incubated with target cells (K562, K562 CD20 or Raji cells) at ratios of 10:1 and 5:1 for 24 h, and the killing rate was estimated by an LDH cytotoxicity assay. To evaluate the effect of CAR-T20 on the survival time of tumor-bearing animals, 30 NSG mice were employed, and Raji-Luc cells (5 × 105 cells per mouse) were administered prior to CAR-T20 administration. The survival time, optical intensity of Raji-Luc cells, clinical symptoms, and body mass of the animals were observed. Another 144 male NSG mice were employed to investigate the proliferation and antitumor effects of CAR-T20. Human cytokine and murine cytokines were detected at 1, 7, 14, 21, 28, 42, 56 and 90 days post-CAR-T administration, while biochemistry index analysis, T-cell and CAR-T-cell detection in peripheral blood, and histopathological examination were performed at 14, 28, 56 and 90 days post-administration.ResultsCAR-T20 cells had a specific killing effect on CD20-expressing cells in vitro. At a dose of 1 × 106 per mouse or above, CAR-T20 prolonged the median survival time from 14 days to more than 3 months, inhibited the proliferation of Raji cells in mice, and alleviated the clinical manifestations and weight loss caused by the Raji-Luc cell load. CAR-T20 at a dose of 2 × 106 per mouse or above inhibited the proliferation of Raji cells in mice for up to 111 days post-administration without recurrence. The numbers of T cells and CAR-T cells in the animals administered CAR-T20 increased significantly when Raji cells were markedly proliferated and subsequently decreased when Raji cells were predominantly inhibited. CAR-T20 increased human IFN-γ, murine TNF and murine IL-6 levels and decreased human IL-10 levels in tumor-bearing mice. The incidences of xenografted tumors in organs/tissues were also reduced effectively by CAR-T20.ConclusionThe effective dose of CAR-T20 in mice starts from 1 × 106 per mouse, equivalent to a clinical dose of 5 × 106/kg. Together, our data support the clinical translation of CAR-T20 for R/R B-cell NHL patients.

Project description:PurposeHigh tumor burden has emerged as a negative predictor of efficacy in chimeric antigen receptor T-cell therapy (CART) in patients with refractory or relapsed large B-cell lymphoma. This study analyzed the deviation among imaging-based tumor burden (TB) metrics and their association with progression-free (PFS) and overall survival (OS).Materials and methodsIn this single-center observational study, we included all consecutively treated patients receiving CD19 CART with available baseline PET-CT imaging. Imaging-based TB was determined based on response evaluation criteria in lymphoma (RECIL), the Lugano criteria, and metabolic tumor volume. Total, nodal and extranodal TB were represented, according to the respective criteria, by sum of longest diameters (TBRECIL), sum of product of perpendicular diameters (TBLugano), and metabolic tumor volume (TBMTV). Correlation statistics were used for comparison. Proportional Cox regression analysis studied the association of TB metrics with PFS and OS.Results34 consecutive patients were included (median age: 67 years, 41% female) with total median baseline TBRECIL of 12.5 cm, TBLugano of 4,030 mm2 and TBMTV of 330 mL. The correlation of TBRECIL and TBLugano with TBMTV was strong (ρ=0.744, p<0.001 and ρ=0.741, p<0.001), with lowest correlation for extranodal TBRECIL with TBMTV (ρ=0.660, p<0.001). Stratification of PFS was strongest by total TBMTV>50% (HR=2.915, p=0.042), whereas total TBRECIL>50% and total TBLugano>50% were not significant (both p>0.05). None of the total TB metrics were associated with OS (all p>0.05).ConclusionPre-CART TB metrics vary significantly based on the assessment method, impacting their association with survival outcomes. The correlation between TBRECIL, TBLugano and TBMTV was influenced by disease phenotype and prior bridging therapy. TB method of assessment must be considered when interpreting the impact of TB on outcomes in clinical trials. Considering the heterogeneity, our results argue for standardization and harmonization across centers.

Dataset Information

Tumor Antigen and Receptor Densities Regulate Efficacy of a Chimeric Antigen Receptor Targeting Anaplastic Lymphoma Kinase.

Publications

Tumor Antigen and Receptor Densities Regulate Efficacy of a Chimeric Antigen Receptor Targeting Anaplastic Lymphoma Kinase.

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