Adoptive Transfer of Cytotoxic T Lymphocytes Targeting Two Different Antigens Limits Antigen Loss and Tumor Escape

Abstract

An antitumor T-cell response can lead to tumor control without clearing all tumor cells. As long as residual tumor cells remain, there is a constant risk of escape from that T-cell response. We previously showed that adoptive transfer of anti-ova OT-I T cells into B16ova-bearing mice led to tumor regression followed by escape of tumors that had lost the ova gene, rendering the OT-I T cells ineffective. In this study, we hypothesized that simultaneous transfer of cytotoxic T lymphocytes targeted against two independent antigens would reduce selection for single-antigen-loss cells, thereby limiting tumor escape. Using OT-I and Pmel T cells to treat B16ova tumors, we found that early cotransfer could prevent tumor emergence in most mice, whereas neither T-cell specificity alone was able to do so. When combined with total body irradiation for the treatment of larger 7-day tumors, cotransfer was also better at limiting tumor recurrence, and the tumors that did escape combination therapy continued to express both target antigens. As adoptively transferred T cells also persisted in vivo, even in mice with recurrent tumors, we hypothesized that restimulation of these antitumor T cells would prolong survival of mice with recurrent tumors. Consistent with this hypothesis, administration of a low-dose regimen of cyclophosphamide following tumor escape slowed tumor growth in mice that had previously received T-cell therapy, but not in control-treated mice, an effect that was associated with increased activation of T cells in vitro by low-but not high-dose cyclophosphamide.

Adenovirus Improves the Efficacy of Adoptive T-cell Therapy by Recruiting Immune Cells to and Promoting Their Activity at the Tumor

“…2B). According to earlier reports (22,23), using even higher cell numbers in adoptive transfer does not translate into long-term survival of B16.OVA-bearing mice, highlighting the immunosuppressive nature of the model, which is in accord with clinical observations suggesting a lack of efficacy in T-cell therapies used as single agents for the treatment of solid tumors. Keeping in mind that human adenovirus does not productively replicate in or lyse murine B16.OVA cells, the observed synergy between adenovirus and the transferred T cells was likely the result of favorable immune responses instigated by infection per se.…”

CD8+ T-cell Responses Rapidly Select for Antigen-Negative Tumor Cells in the Prostate

“…Our findings suggest that targeting multiple epitopes in poorly immunogenic tumors may increase the efficacy of immunotherapies. Indeed, in a B16-OVA model where treatment of mice with OT-1 T cells was unable to control tumor growth (6), treatment with both OT-1 and the gp-100 specific Pmel-1 T cells prevented tumor growth (21). Furthermore, our work suggests that targeting of oncogenic drivers of tumor growth with immunotherapy could be a more productive strategy.…”

Subversion of NK-cell and TNFα Immune Surveillance Drives Tumor Recurrence

“…The B16ova cell line was derived from a B16.F1 clone transfected with a pcDNA3.1ova plasmid (33). B16ova cells were grown in DMEM (HyClone) containing 10% FBS (Life Technologies) and G418 (5 mg/mL; Mediatech) until challenge.…”

“…Thus, treatment of either subcutaneous B16 melanoma or TC2 prostate tumors with adoptive T-cell transfer (21, 33–35), systemic virotherapy (36, 37), VSV-cDNA immunotherapy (38, 39), or ganciclovir chemotherapy (40–42) led to apparent tumor clearance (no palpable tumor) for > 40 to 150 days. However, with prolonged follow-up, a proportion of these animals developed late, aggressive local recurrences, mimicking the clinical situation in multiple tumor types (43–45).…”