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338 Comparison of lymphodepleting chemotherapy regimens as preconditioning for T-cell therapies
  1. Oleg Demin1,
  2. Galina Kolesova2,
  3. Natalia Ramos-Hernandez3,
  4. Thomas Faitg3,
  5. Stefan Zajic3 and
  6. Lourdes Cucurull-Sanchez4
  1. 1InSysBio CY, Pafos, Cyprus
  2. 2InSysBio, Moscow, Russian Federation
  3. 3GlaxoSmithKline, Collegeville, PA, USA
  4. 4GlaxoSmithKline, Stevenage, UK
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.

Abstract

Background Lymphodepleting chemotherapy is typically to patients prior to cell infusion to promote expansion, persistence, and function of adoptively transferred engineered T-cells. Various regimens and doses of are used. Lymphodepletion therapy works by multiple mechanisms, including the elimination of sinks for homeostatic cytokines, such as interleukin-7 (IL-7) and interleukin-15 (IL-15), caused by depletion of endogenous lymphocytes. We applied semi-mechanistic mathematical modeling to compare different lymphodepletion regimens by simulating absolute lymphocyte count (ALC) and IL-7 and IL-15 levels in patients at the time of engineered T-cell infusion (table 1).

Methods The developed mathematical model describes pharmacokinetics (PK) of the 2 drugs fludarabine and cyclophosphamide, their effects on lymphocyte (T-cells) depletion, and contribution of T-cells in the degradation of IL-7 and IL-15. PK models and parameters of fludarabine and cyclophosphamide were taken from published models.1 2 These models were updated to describe the impact of creatinine clearance (CrCl) on the clearance of both drugs, and were validated against PK data in patients with renal impairment. Fludarabine and cyclophosphamide effects on ALC, IL7 and IL15 were fitted and validated against clinical data reported on monotherapies and their combination.3–7

Results Two regimens similar to regimen 3 but with a reduced dose of fludarabine were tested for patients with mild and moderate renal impairment. The most effective regimen in patients with normal renal function was regimen 1 (fludarabine 30 mg/m2/day for 4 days and cyclophosphamide 1800 mg/m2/day for 2 days) followed by regimen 6 (fludarabine 30 mg/m2/day for 3 days and cyclophosphamide 500 mg/m2/day for 3 days). Regimen 1 resulted in the lowest ALC at the time of T-cell infusion (median = 0.032*109 cell/L). The highest IL-7 level was observed for regimen 1 (median = 28.93 pg/mL), whereas the highest IL-15 level was observed for regimen 6 (median = 19.693 pg/mL). Regimen 2, consisting of two doses of cyclophosphamide, showed substantially higher ALC and lower levels of IL-7 and IL-15. Regimens for patients with renal impairment showed almost the same ALC and cytokine levels as regimen 3.

Conclusions The most effective regimen of lymphodepletion in terms of ALC decrease and cytokines increase was predicted to be fludarabine 30 mg/m2/day for 4 days and cyclophosphamide 1800 mg/m2/day for 2 days. However, there was no substantial difference between tested regimens except regimen 2 showed the lowest efficacy.

References

  1. Salinger, et al. A limited sampling schedule to estimate individual pharmacokinetic parameters of fludarabine in hematopoietic cell transplant patients. Clin Cancer Res. 2009 Aug 15;15(16):5280–7.

  2. Chen, et al. Nonlinear pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide in patients with metastatic breast cancer receiving high-dose chemotherapy followed by autologous bone marrow transplantation. Drug Metab Dispos. 1997 May;25(5):544–51.

  3. Ramachandran, et al. Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma. J Immunother Cancer. 2019 Oct 24;7(1):276.

  4. Condomines, et al. Functional regulatory T cells are collected in stem cell autografts by mobilization with high-dose cyclophosphamide and granulocyte colony-stimulating factor. J Immunol. 2006 Jun 1;176(11):6631–9.

  5. McCune, et al. Association of fludarabine pharmacokinetic/dynamic biomarkers with donor chimerism in nonmyeloablative HCT recipients. Cancer Chemother Pharmacol. 2015 Jul;76(1):85–96.

  6. Kochenderfer, et al. Lymphoma Remissions Caused by Anti-CD19 Chimeric Antigen Receptor T Cells Are Associated With High Serum Interleukin-15 Levels. J Clin Oncol. 2017 Jun 1;35(16):1803–1813.

  7. Heczey, et al. CAR T Cells Administered in Combination with Lymphodepletion and PD-1 Inhibition to Patients with Neuroblastoma. Mol Ther. 2017 Sep 6;25(9):2214–2224.

Abstract 338 Table 1

Regimens simulated by the model.

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