TY - JOUR

T1 - Bone marrow toxicity and immune reconstitution in melanoma and non-melanoma solid cancer patients after non-myeloablative conditioning with chemotherapy and checkpoint inhibition

AU - Kverneland, Anders H.

AU - Borch, Troels Holz

AU - Granhøj, Joachim

AU - Sengeløv, Henrik

AU - Donia, Marco

AU - Svane, Inge Marie

N1 - Publisher Copyright: © 2021 International Society for Cell & Gene Therapy

PY - 2021/8

Y1 - 2021/8

N2 - Background aims: Lymphodepletion with non-myeloablative (NMA) chemotherapy is currently a prerequisite for adoptive cell therapy (ACT). ACT based on tumor-infiltrating lymphocytes has long been used in malignant melanoma (MM), but with the advance of ACT into new cancer diagnoses, the patient predisposition will change. The authors here evaluate the bone marrow (BM) toxicity of NMA in combination with checkpoint inhibition and a priori risk factors in a wide range of cancer diagnoses. Methods: Thirty-one non-MM and MM patients were included from two different clinical trials with ACT. The treatment history was extracted from the medical records, together with the hematology data. Immune monitoring with flow cytometry was performed before and at several time points after therapy. Results: NMA induced reversible myelosuppression in all patients. No significant differences in BM toxicity between MM and non-MM patients were found. The overall hematology counts were reconstituted within 3–6 months but with great individual heterogeneity, including eight patients who developed a second phase of neutropenia after hospital discharge. A performance status >0 was found, and shorter overall survival and sex were statistically associated with longer duration of anemia. By contrast, high expression of co-stimulatory markers CD28+ and CD27+ on T cells at baseline was significantly correlated with shorter duration of neutropenia (P = 0.010 and P = 0.009, respectively), anemia (P = 0.001 and P = 0.001, respectively) and thrombocytopenia (P = 0.017 and P = 0.030, respectively). In addition, following NMA, the authors saw a significant differentiation of T-cell phenotype associated with old age. Conclusions: ACT with NMA and checkpoint inhibition is tolerable in patients with multiple cancer diagnoses and therapy backgrounds but comes with substantial transient BM toxicity that is comparable in both non-MM and MM patients. Baseline T-cell CD28/CD27 expression level is predictive of duration of BM toxicity. Furthermore, NMA conditioning induces changes in the immune system that may affect a patient's immunocompetence for many months following therapy.

AB - Background aims: Lymphodepletion with non-myeloablative (NMA) chemotherapy is currently a prerequisite for adoptive cell therapy (ACT). ACT based on tumor-infiltrating lymphocytes has long been used in malignant melanoma (MM), but with the advance of ACT into new cancer diagnoses, the patient predisposition will change. The authors here evaluate the bone marrow (BM) toxicity of NMA in combination with checkpoint inhibition and a priori risk factors in a wide range of cancer diagnoses. Methods: Thirty-one non-MM and MM patients were included from two different clinical trials with ACT. The treatment history was extracted from the medical records, together with the hematology data. Immune monitoring with flow cytometry was performed before and at several time points after therapy. Results: NMA induced reversible myelosuppression in all patients. No significant differences in BM toxicity between MM and non-MM patients were found. The overall hematology counts were reconstituted within 3–6 months but with great individual heterogeneity, including eight patients who developed a second phase of neutropenia after hospital discharge. A performance status >0 was found, and shorter overall survival and sex were statistically associated with longer duration of anemia. By contrast, high expression of co-stimulatory markers CD28+ and CD27+ on T cells at baseline was significantly correlated with shorter duration of neutropenia (P = 0.010 and P = 0.009, respectively), anemia (P = 0.001 and P = 0.001, respectively) and thrombocytopenia (P = 0.017 and P = 0.030, respectively). In addition, following NMA, the authors saw a significant differentiation of T-cell phenotype associated with old age. Conclusions: ACT with NMA and checkpoint inhibition is tolerable in patients with multiple cancer diagnoses and therapy backgrounds but comes with substantial transient BM toxicity that is comparable in both non-MM and MM patients. Baseline T-cell CD28/CD27 expression level is predictive of duration of BM toxicity. Furthermore, NMA conditioning induces changes in the immune system that may affect a patient's immunocompetence for many months following therapy.

KW - adoptive cell therapy

KW - conditioning chemotherapy

KW - non-myeloablative conditioning

KW - tumor-infiltrating lymphocytes

U2 - 10.1016/j.jcyt.2021.03.003

DO - 10.1016/j.jcyt.2021.03.003

M3 - Journal article

C2 - 33933372

AN - SCOPUS:85104970896

VL - 23

SP - 724

EP - 729

JO - Cytotherapy

JF - Cytotherapy

SN - 1465-3249

IS - 8

ER -