Adoptive cellular immunotherapy of cancer in mice using allogeneic T-cells

Abstract

Background: Adoptive cellular immunotherapy with autologous tumor-infiltrating lymphocytes (TILs) can induce tumor regression in patients with metastatic melanoma but requires both surgical tumor harvest and successful expansion of lymphocytes in vitro. In cases in which tumors are inaccessible or TILs fail to grow, the adoptive transfer of allogeneic TILs, haplotype matched for the restriction element for a common tumor antigen, represents a possible treatment alternative. Such TILs show in vitro cross-reactivity for allogeneic tumors but have not been evaluated for in vivo activity.

Methods: An F1 hybrid mouse (C57BL/6 X DBA-2[B6D2 F1]) was used to generate TILs (F1 TILs) expressing both H-2b and H-2d class I major histocompatibility complex (MHC) determinants, which were used to treat established autologous lung metastases in C57BL/6 (B6) parental strain mice.

Results: H-2b mice bearing the fully syngeneic MC-38 tumor were treated with F1 TILS, and a 98-100% reduction in 4-day-old established lung metastasis was achieved. However, B6 mice bearing MC-38 tumors after preimmunization with H-2d splenocytes did not show a response to F1 TILs. Preimmunization of B6 mice by intravenous injection of H-2d splenocytes at varying times before F1 TIL administration showed a dramatic reduction in F1 TIL efficacy when alloimmunization occurred as early as 2 days before therapy. Immunization against an unrelated haplotype (H-2s) sharing no MHC genes with the F1 TILs resulted in a smaller reduction of F1 TIL efficacy, possibly due to shared minor determinants.

Conclusion: Allogeneic TILs sharing an MHC restriction element for a common tumor antigen can be used to successfully treat established metastases in the nonallosensitized host.