COMBINATION Therapies Including TOCILIZUMAB Decrease the Progression of CLAD: Initial Clinical Experience

Purpose TH17 & IL-6 interactions and detrimental Biologic effects may mediate CLAD / BOS in a murine Lung allograft model and Human LT. TOCILIZUMAB (TCZ), a humanized monoclonal Ab targets the IL-6 receptor subunit alpha (IL-6Rα), preventing binding of IL-6 to both IL-6R and signal transducer glycoprotein 130 complex, hence inhibiting downstream signaling (JAK-STAT). Pertinent to potential therapeutic considerations for CLAD, TCZ decreases circulating PMNs, Monocytes, MIF & TH-17 cells and increases TREG & Regulatory B-Lymphocytes. We review our initial TCZ experience with COMBINATION immunotherapies for CLAD. Methods Review LT recipients who received ≥ 3 mos TCZ (4-8 mg/Kg/month) treatment for CLAD. Analysis: (SPIROM) Linear Regression Slope FEV-1 (mL/month), infection incidence, Single Antigen Flow Cytometry HLA Class I & II Donor-specific ALLO-Antibodies (DSA) and Non-HLA Antibodies (EC-1&2, AT1R). Baseline Interleukin-6 (IL-6) Serum values (Quantitative multiplex assay; ARUP Labs, Inc.) were measured (NL: ≤ 5 pg/mL). Values expressed as (Median ± SD) / Paired T-test. Results N=9 [BLT (4), SLT (4), Lung-Liver (1)]; Ages: 65 (23-75) years; M: F (7:2); Time Post-LT: 28 ± 30.9 mos. [4-102]. CLAD Stages: BOS I (2), II (4), III (2), RAS (1). CLAD therapies: Rabbit ATG (5), Rituximab (1), IVIG (9) + TCZ. Baseline DSA (PRE- treatment): HLA Class I (2), Class II (6) in N=6 patients; EC1&2 (6) and AT1R (1). All DSA were Weak or Moderate MFI (< 5000). Serum IL-6 levels: 11.0 ± 16.2 pg/mL. SPIROM: PRE- (3-6 mos.) Median SLOPE: -130 ± 157 mL/month and POST- (6-12 mos.) +19.3 ± 56.8 (P<0.001). Deaths related to BOS III (1) and Cardiac event (1). Potential opportunistic infection occurred in one patient (Aspergillus). F/U HLA Class I & II DSA were no longer detectable in 5 patients (83%) while EC-1&2 Abs persisted in all patients. Conclusion 1. Initial experience suggested COMBINATION therapies for CLAD including TCZ, with different therapeutic targets, can stabilize SPIROM Decline without apparent significant Adverse Effects. 2. DSA HLA Class I & II (<5000 MFI) decreased with treatment. 3. TCZ effects on detrimental IL-6 / TH-17 Biology may represent an alternative treatment strategy to Extra-corporeal Photopheresis (ECP) for CLAD/BOS. 4. COMBINATION Therapies for CLAD would be appropriate for Multi-Center Clinical Trials. TH17 & IL-6 interactions and detrimental Biologic effects may mediate CLAD / BOS in a murine Lung allograft model and Human LT. TOCILIZUMAB (TCZ), a humanized monoclonal Ab targets the IL-6 receptor subunit alpha (IL-6Rα), preventing binding of IL-6 to both IL-6R and signal transducer glycoprotein 130 complex, hence inhibiting downstream signaling (JAK-STAT). Pertinent to potential therapeutic considerations for CLAD, TCZ decreases circulating PMNs, Monocytes, MIF & TH-17 cells and increases TREG & Regulatory B-Lymphocytes. We review our initial TCZ experience with COMBINATION immunotherapies for CLAD. Review LT recipients who received ≥ 3 mos TCZ (4-8 mg/Kg/month) treatment for CLAD. Analysis: (SPIROM) Linear Regression Slope FEV-1 (mL/month), infection incidence, Single Antigen Flow Cytometry HLA Class I & II Donor-specific ALLO-Antibodies (DSA) and Non-HLA Antibodies (EC-1&2, AT1R). Baseline Interleukin-6 (IL-6) Serum values (Quantitative multiplex assay; ARUP Labs, Inc.) were measured (NL: ≤ 5 pg/mL). Values expressed as (Median ± SD) / Paired T-test. N=9 [BLT (4), SLT (4), Lung-Liver (1)]; Ages: 65 (23-75) years; M: F (7:2); Time Post-LT: 28 ± 30.9 mos. [4-102]. CLAD Stages: BOS I (2), II (4), III (2), RAS (1). CLAD therapies: Rabbit ATG (5), Rituximab (1), IVIG (9) + TCZ. Baseline DSA (PRE- treatment): HLA Class I (2), Class II (6) in N=6 patients; EC1&2 (6) and AT1R (1). All DSA were Weak or Moderate MFI (< 5000). Serum IL-6 levels: 11.0 ± 16.2 pg/mL. SPIROM: PRE- (3-6 mos.) Median SLOPE: -130 ± 157 mL/month and POST- (6-12 mos.) +19.3 ± 56.8 (P<0.001). Deaths related to BOS III (1) and Cardiac event (1). Potential opportunistic infection occurred in one patient (Aspergillus). F/U HLA Class I & II DSA were no longer detectable in 5 patients (83%) while EC-1&2 Abs persisted in all patients. 1. Initial experience suggested COMBINATION therapies for CLAD including TCZ, with different therapeutic targets, can stabilize SPIROM Decline without apparent significant Adverse Effects. 2. DSA HLA Class I & II (<5000 MFI) decreased with treatment. 3. TCZ effects on detrimental IL-6 / TH-17 Biology may represent an alternative treatment strategy to Extra-corporeal Photopheresis (ECP) for CLAD/BOS. 4. COMBINATION Therapies for CLAD would be appropriate for Multi-Center Clinical Trials.