Bedside to bench and back again: how animal models are guiding the development of new immunotherapies for cancer

Abstract

Immunotherapy using adoptive cell transfer is a promising approach that can result in the regression of bulky, invasive cancer in some patients. However, currently available therapies remain less successful than desired. To study the mechanisms of action and possible improvements in cell-transfer therapies, we use a murine model system with analogous components to the treatment of patients. T cell receptor transgenic CD8+ T cells (pmel-1) specifically recognizing the melanocyte differentiation antigen gp100 are adoptively transferred into lympho-depleted mice bearing large, established, 14-day subcutaneous B16 melanoma (0.5-1 cm in diameter) on the day of treatment. Adoptive cell transfer in combination with interleukin interleukin-2 or interleukin-15 cytokine administration and vaccination using an altered form of the target antigen, gp100, can result in the complete and durable regression of large tumor burdens. Complete responders frequently develop autoimmunity with vitiligo at the former tumor site that often spreads to involve the whole coat. These findings have important implications for the design of immunotherapy trials in humans.

Fig. 1

Diagram of pmel-1 CD8⁺ transgenic T cell interaction with B16 melanoma. T cells from transgenic mice express a TCR recognizing a H-2D^b-restricted CD8⁺ epitope from the gp100/pmel-17 protein mouse gp100_25–33 (EGSRNQDWL) or human gp100_25–33 (KVPRNQDWL). APC, Antigen-presenting cell.

Fig. 2

Successful treatment of lung nodules. Adoptive cell transfer of 1 × 10⁶ fresh pmel-1 CD8⁺ T splenocytes was undertaken in combination with recombinant (r)hIL-2 cytokine administration at 36 μg doses intraperitoneally (i.p.), twice a day for 3 days, and a fowlpox virus encoding human gp100 (rFPVhgp100) into wild-type C57BL/6 mice 7 days after establishment of lung nodules. Kaplan-Meier survival curves illustrating significant survival benefit from with complete treatment regimen.

Fig. 3

Development of an analogous model to the treatment of human patients. Schema for treatment regimen of 14-day s.c. B16 melanoma.

Fig. 4

Implications from the animal model. Adoptive cell transfer of pmel-1 CD8⁺ T splenocytes was undertaken alone or in combination with rhIL-2 cytokine administration at 36 μg doses i.p., twice a day for 3 days, and/or a fowlpox virus encoding human gp100 (rFPVhgp100) into sublethally irradiated C57BL/6 mice bearing 14-day, established s.c. B16 melanoma. (A) Dramatic tumor regression was observed only in mice receiving the complete treatment regimen consisting of adoptive transfer of 1 × 10⁶ fresh pmel-1 cells, rFPVhgp100 vaccine, and IL-2 (▪). (B) Complete regression of large tumor burden was achieved in mice receiving adoptive transfer of 2 × 10⁷ fresh pmel-1 cells, rFPVhgp100 vaccine, and IL-2 (▪).

Fig. 5

Optimal treatment led to complete regression of large tumors and autoimmunity. Vitiligo at the former tumor site continued to spread to involve the entire coat.