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P-18.31 Analysis of Immunobiogram pharmacodynamic dose-response curves to immunosuppressants in kidney transplant recipients: Further results from Transbio Study

Julio Pascual, Spain

Chief
Nephrology Department and Kidney Transplantation Program
Parc de Salut Mar

Abstract

Analysis of Immunobiogram pharmacodynamic dose-response curves to immunosuppressants in kidney transplant recipients: Further results from Transbio Study

Julio Pascual1, Carlos Jiménez2, Magdalena Krajewska3, Daniel Seron 4, Camille Kotton 5, Jose María Portolés6, Oliver Witzke7, Soren S. Sorensen8, Amado Andrés 9, Teresa Diez 10, Álvaro Ortega 10, Isabel Portero 10.

1Nephrology Department and Kidney Transplantation, Hospital del Mar, Barcelona, Spain; 2Nephrology Department, Hospital La Paz, Madrid, Spain; 3Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw , Poland; 4Nephrology Department, Hospital Vall d’Hebron, Barcelona, Spain; 5Transplant Infectious Diseases Division, Massachusetts General Hospital, Boston , MA, United States; 6Nephrology Department, Hospital Puerta de Hierro, Madrid, Spain; 7Department of Infectious Diseases, University Hospital Essen, University Duisburg-Essen, Essen, Germany; 8Nephrology Department, Rigshospitalet, Copenhagen , Denmark; 9Nephrology Department, Hospital 12 de Octubre, Madrid, Spain; 10Biohope Scientific Solutions for Human Health, Madrid, Spain

Introduction: Immunobiogram (IMBG) is a novel pharmacodynamic immune function assay developed by Biohope to measure in vitro the sensitivity/resistance (S/R) profile of each patient’s lymphocytes when exposed to a panel of immunosuppressive drugs (IS).
TRANSBIO is an international, multicenter study to evaluate IMBG in patients at least one year after Kidney Transplantation (KT) and main study results have been presented elsewhere.
S/R profile is obtained first from dose/response curves for each IS tested, evaluated by several Key Curve Parameters (KCP), which are then translated into a Resistance Map.
In this analysis, the dose-response curves obtained in patient subsamples treated with Mycophenolate (MMF) or Tacrolimus (TAC) were analyzed to identify the KCP capable to predict clinical outcome.
Materials and Methods: IMBG involves culture of patient PBMCs in a semi-solid 3D matrix, then submitted to immune stimulation. It reveals the capacity of an IS over a dose gradient to inhibit the activation&proliferation of lymphocytes through dose-response curves, mathematically analyzed by a software. The normalized KCP analyzed are: Initial Response (IR), Final Response (FR) (immune response measured at maximal and minimal IS concentration points), Area under the curve (AUC), ID50 and Slope.
KCPs were compared between patients with a Bad-Clinical-Evolution (BCE) (according to clinical outcomes and immune-biomarkers in previous 12-18 months) and Good-Clinical-Evolution (GCE) in patients treated with MMF or TAC.
Results: From 103 patients, 85 were taking MMF.  2-sample t test showed a significant difference between mean values of IR, FR and AUC between patients with BCE vs GCE (p<0.05).
In patients treated with TAC (n=85) there was a significant difference in ID50 mean between patients with BCE vs GCE (p<0.05).
In logistic regression analysis, IR, FR and AUC for MMF and ID50 for TAC treated patients were statistically significant associated with a bad prognosis (p<0,05). When adjusted for simultaneous corticosteroids intake as confounding factor, IR and AUC for MMF and ID50 for TAC remained significantly associated with prognosis.
Discussion: KCP obtained from IMBG dose-response curves for TAC and MMF are significantly associated with clinical outcome, which probably is capturing the effect of medication over causality. There is a different profile in the KCPs most informative for TAC and MMF, what can be linked to a diverse impact of these drugs over lymphocytes proliferation (MMF) or activation (TAC). Models should always be adjusted for corticosteroids intake.
Conclusion: In kidney transplanted patients, dose-response curves obtained with IMBG are significantly associated with clinical outcome. Different curve parameters are better descriptors of this association depending on the IS, what could be linked with their mechanism of action.

European Union Horizon 2020 Programme for Research and Innovation - SME instrument Phase 2 - Grant agreement Nº 733248.

References:

[1] Pascual J et al. Analytical robustness and clinical consistency evaluation of a new in vitro diagnostic biotechnological immunoassay to help decision-making in adjustment of immunosuppressant therapy for kidney transplantation: TRANSBIO STUDY. Transplant International 2019; 32(Suppl. 2): 279–319
[2] Fallahi-Sichani M et al. Metrics other than potency reveal systematic variation in responses to cancer drugs. Nat Chem Biol. 2013 Nov; 9(11): 708–714.

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