Ex vivo gene transfer for improved adoptive immunotherapy of cancer

Abstract

Adoptive immunotherapy is an appealing approach to cancer treatment, with the potential for more precise targeting and reduced toxicity. While early clinical trial data using adoptive T cells against post-transplant virus-associated hematologic malignancies, lymphoma and melanoma have been promising, treating other solid tumors has proven to be more challenging. Adoptive lymphocytes have been genetically modified in many ways to improve activity and circumvent tumor evasion, including transfer of transgenic T-cell receptors and chimeric antigen receptors to redirect T cell and natural killer cell antigen specificity. Gene transfer may also allow expression of homeostatic cytokines or their receptors to overcome the lack of stimulatory signals or expression of dominant-negative receptors for inhibitory cytokines to compensate for an immunosuppressive tumor milieu. In addition, suicide genes can install a 'safety switch' on adoptively transferred cells to allow ablation if necessary. Although further refinement and validation are necessary, these genetic modification strategies offer hope for significant improvements in cancer immunotherapy.

Fine-tuning Tumor Immunity with Integrin Trans-regulation

“…T cell migration to solid tumors is important for tumor immunity (1), whereas tumor infiltration by macrophages may promote tumor growth through increased angiogenesis and suppressed immunity (2, 3). In adoptive immunotherapy (11–14, 19), naïve T cells are modified and activated in vitro ; however T cell homing is a critical limiting variable in solid tumor adoptive immunotherapy (9, 10). Based on our results with the peritonitis model, we hypothesized that α4(S988A) mice may have increased ability to resist tumors due to selective migration of lymphocytes to the tumor site.…”

“…Inhibiting Focal Adhesion Kinase (FAK) can suppress such trans-regulation (8), a finding that sounds a cautionary note in the use of FAK inhibitors in tumor therapy (26–28) and suggests that the effect of these agents on lymphocyte trafficking to tumors should be evaluated. Homing of infused lymphocytes is currently a rate-limiting step in applying T cell immunotherapy to solid tumor cancers (9). Since lymphocytes are modified ex vivo before adoptive transfer for immunotherapy (11–14), the opportunity exists to simultaneously optimize their homing capacity by increasing integrin trans-regulation.…”

“…We found that the α4(S988A) mutation markedly increased the abundance of T cells but not myeloid cells in heterotopic B16 melanomas. Increased lymphocyte homing is needed for efforts to develop adoptive immuno-therapies for solid tumors (9–14). The potential therapeutic value of this form of integrin trans-regulation was established by the finding that subcutaneously implanted melanomas grew more slowly in α4(S988A) mice associated with markedly enhanced recruitment of T cells but not myeloid cells to the tumors.…”

Cellular immunotherapy for malignant gliomas

“…The Ab is linked to the CD3ζ chain and other T cell activation pathways, allowing T cell activation and target cell killing 77, 78 . In addition, Abs bind antigens with much greater affinity than do TCRs, resulting in the formation of a more stable immunological synapse 79 .…”

Dynamic analysis of an antitumor model and investigation of the therapeutic effects for different treatment regimens

“…Adoptive cell transfer therapy (ACT) is an immunotherapy method and has already demonstrated a good development prospect. Recent clinical trials have manifested that ACT immunotherapy with antitumor lymphocytes can cause cancer cell apoptosis in approximately 70 % of patients with metastatic melanoma (Ngo et al 2011). Hence, in vitro manipulation of antitumor immunity can be effectively applied in the treatment of cancer patients (Rosenberb et al 2008;Restifo et al 2012).…”