Adoptive T cell therapy promotes the emergence of genomically altered tumor escape variants

Abstract

Adoptive T cell therapy has proven effective against melanoma in mice and humans. However, because most responses are incomplete or transient, cures remain rare. To maximize the efficacy of this therapy, it will be essential to gain a better understanding of the processes which result in tumor relapse. We studied these processes using B16ova murine melanoma and adoptive transfer of OT-I T cells. Transfer of T cells as a single therapy provided a significant survival benefit for mice with established subcutaneous tumors. However, tumors which initially regressed often recurred. By analyzing tumors which emerged in the presence of a potent OT-I response, we identified a novel tumor escape mechanism in which tumor cells evaded T cell pressure by undergoing major genomic changes involving loss of the gene encoding the target tumor antigen. Furthermore, we show that these in vivo processes can be recapitulated in vitro using T cell/tumor cell co-cultures. A single round of in vitro co-culture led to significant loss of the ova gene and a tumor cell population with rapidly induced and diverse karyotypic changes. Although these current studies focus on the model OVA antigen, the finding that T cells can directly promote genomic instability has important implications for the development of adoptive T cell therapies.

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.…”

Molecular Pathways: Multimodal Cancer-Killing Mechanisms Employed by Oncolytic Vesiculoviruses

“…For several reasons, however, this approach has proven more challenging, including the facts that (1) real self-tumor antigens are relatively weak as the host is tolerized towards them and contains very few T-cell precursors (39); (2) the selective pressure applied by immune therapies towards a single tumor antigen can lead to escape variants (44), and (3) OVs are extremely immunogenic themselves and may distract the immune system from the tumor (34,45). To address aspects of these barriers, two innovative approaches have recently been developed.…”

Immunotherapy-induced CD8+ T Cells Instigate Immune Suppression in the Tumor

“…In that context, the immune suppressive nature of the tumor reflects the history of immune-mediated attack on the cancerous cells. It has been shown that immunotherapies cause further editing of the tumor and promote the outgrowth of tumor escape variants; 19,20 however, whether immunotherapies also influence the immune suppressive pathways in the tumor remains to be elucidated.…”