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Biology subjects

Del Principe, M. I.

Publications and source records attributed to Del Principe, M. I..

3 recordsLinked to original sources

Model-based Bayesian inference of cancer dynamics from heterogenous longitudinal data

The kinetic parameters of cancer population dynamics are critical for developing reliable predictors of tumour growth patterns, extracting metrics for patient stratification and creating algorithms that can forecast clinically significant events. Here, we introduce a model-based Bayesian framework that leverages longitudinal phenotypic (e.g., tumour volume, cell counts) or genotypic (e.g., mutation frequency) data to infer critical parameters of tumour progression within a single patient. Our models uses population genetics to estimate probability distributions for tumour growth rates, initiation and extinction times, pinpointing abrupt shifts in tumour dynamics due to treatment response and revealing associations between drug resistance and pre-existing cancer cell populations. We apply our framework to address pivotal clinical questions across three major cancer types. In colorectal cancer, we use tumour markers data to identify extensive pre-existing RAS-linked resistance to cetuximab. In lung cancer, we use somatic mutation frequencies in citculating tumour DNA to determine prognostic growth rates and develop a test for monitoring minimal residual disease. In chronic lymphocytic leukaemia, we use white blood cell counts to stratify patients by growth patterns and predict time to treatment, advancing adaptive monitoring strategies.

cancer biology↗

ANTIBODY-INDEPENDENT ANTITUMOR EFFECTS OF CD32A-CHIMERIC RECEPTOR T CELLS: IMPLICATIONS FOR BREAST CANCER PROGNOSIS AND TREATMENT.

Fc{gamma} RIIA (CD32A) and their ligands, including the immunoglobulin Fc fragment and pentraxins, are key players in a variety of innate immune responses. Still unclear is whether additional ligands of CD32A do exist. The objective of this study is to demonstrate that CD32A-chimeric receptor (CR) can be utilized for the identification of CD32A cell surface ligand(s). Among fifteen cancer cell lines tested, CD32A-CR T cells recognized three of breast cancer (BC) including the MDA-MB-468 and one colorectal carcinoma (HT29) in the absence of targeting antibodies. Conjugation of sensitive BC cells with CD32A-CR T cells induced CD32A polarization and down-regulation, CD107 release, and mutual cell elimination in vitro. Conversely, normal fibroblasts and myoblasts were not affected while normal HUVEC cells promoted CD32A down-regulation. CD32A-CR T cell activity was not inhibited by human IgGs or human serum, but; it was rather enhanced by cetuximab antibody. RNAseq analysis of sensitive vs resistant BC cells identified a fingerprint of 42 genes predicting the sensitivity of BC cells to CD32A-CR T cells and their association with favorable prognostic significance in advanced BC patients. Our data also identify ICAM 1 as a major regulator of CD32A-CR T cell-mediated cytotoxicity. Finally, CD32A-CR T cell administration protected immunodeficient mice from subcutaneous growth of MDA-MB-468 cells in the absence of tumor-specific antibodies. These data indicate that CD32A-CR can be utilized for the identification of (1) cell surface CD32A ligand(s); (2) rational therapeutic strategies to target BC; and (3) novel transcriptomic signatures prognostically relevant for advanced BC patients.

immunology↗

ELIMINATION OF EGFR-OVEREXPRESSING CANCER CELLS BY CD32 CHIMERIC RECEPTOR T CELLS IN COMBINATION WITH CETUXIMAB OR PANITUMUMAB

Cetuximab and panitumumab bind the human epidermal growth factor receptor (EGFR). While the chimeric cetuximab (IgG1) triggers antibody-dependent-cellular-cytotoxicity (ADCC) of EGFR positive target cells, panitumumab (a human IgG2) does not. The inability of panitumumab to trigger ADCC reflects a poor binding affinity of human IgG2 Fc for the Fc{gamma}RIII (CD16) on NK cells. However, both human IgG1 and IgG2 bind the Fc{gamma}RII (CD32) to a similar extent. Here, we have compared the ability of T cells, engineered with a novel low-affinity CD32131R -chimeric receptor (CR), and those engineered with the low-affinity CD16158F-CR T cells in eliminating EGFR positive epithelial cancer cells (ECCs) in combination with cetuximab or panitumumab. Following T cell transduction, the percentage of CD32131R-CR T cells was (74{+/-}10) significantly higher than that of CD16158F-CR T cells (46{+/-}15). Only CD32131R-CR T cells bound panitumumab. CD32131R-CR T cells combined with the mAb 8.26 (anti-CD32) and CD16158F-CR T cells combined with the mAb 3g8 (anti-CD16) eliminated colorectal carcinoma (CRC), HCT116Fc{gamma}R+ cells, in a reverse ADCC assay in vitro. Cross-linking of CD32131R-CR on T cells by cetuximab or panitumumab and CD16158F-CR T cells by cetuximab induced elimination of triple negative breast cancer (TNBC) MDA-MB-468 cells, and secretion of IFN gamma (IFN{gamma}) and tumor necrosis factor alpha (TNF). Neither cetuximab nor panitumumab induced Fc{gamma}-CR T anti-tumor activity against KRAS-mutated HCT116, non-small-cell-lung-cancer, A549 and TNBC, MDA-MB-231 cells. ADCC of Fc{gamma}-CR T cells was significantly associated with the over-expression of EGFR on ECCs. In conclusion, CD32131R-CR T cells are efficiently redirected by cetuximab or panitumumab against BC cells overexpressing EGFR.\n\nArticle categoryTumor Immunology and Microenvironment\n\nNovelty and ImpactMonoclonal antibody-redirected Fc{gamma}-CR T cell immunotherapy represents a promising approach in the fight against cancer. Here, we expand the application of this methodology to TNBC overexpressing the EGFR utilizing a novel CD32A131R-CR in combination with anti-EGFR mAbs. Our study supports the use of CD32A131R-CR T cells combined with panitumumab or cetuximab for targeting TNBC cells overexpressing the EGFR. Our results may be utilized as a platform for the rational design of therapies targeting TNBC overexpressing EGFR.

immunology↗