Peptide Vaccination after T-Cell Transfer Causes Massive Clonal Expansion, Tumor Eradication, and Manageable Cytokine Storm

Abstract

Adoptive T-cell transfer (ACT) is successfully applied as a cancer treatment that is based on the activation and effector functions of tumor-specific T cells. Here, we present results from a mouse model in which ACT is combined with a long peptide-based vaccine comprising gp100 T-cell epitopes. Transferred CD8 + T cells expanded up to 1,000-fold after peptide vaccination, leading to a 3-fold increase in white blood cell count and a very high frequency in the generation of antigen-specific memory T cells, the generation of which tended to correlate with effective antitumor responses. An enormous pool of effector T cells spread widely to different tissues, including the skin and the immune-privileged eye, where they mediate tumor eradication. Importantly, these striking T-cell dynamics occurred in immunocompetent mice without prior hematologic conditioning. Continued activation of the specific T-cell pool by vaccination led to strong T-cell-mediated cytokine storm and lethality due to multiorgan failure. However, this immunopathology could be prevented by controlling the rapid biodistribution of the peptide or by using a weakly agonistic peptide. Together, these results identify a peptide vaccination strategy that can potently accentuate effective ACT in non-lymphodepleted hosts.

ROS-induced autophagy in cancer cells assists in evasion from determinants of immunogenic cell death

“…27 Such activation leads to increased expansion or proliferation of CD4 + or CD8 + T cells 29 accompanied by IFNG production, 27 processes that have been found to be important for antitumor immunity, ICD and tumor immunogenicity. 11,13,29,30 Interestingly it was recently reported that in the case of chemotherapy-induced ICD, blockage of autophagy can cause ablation of CD4 + or CD8 + T cell immunity. 13 In case of Hyp-PDT induced ICD instead, autophagy attenuation in cancer cells caused superior stimulation of T cells, leading to a significantly increased expansion of the CD4 + or CD8 + T cells.…”

“…27,29,30 To this end, we decided to investigate the effect of autophagy-ablation in cancer cells undergoing Hyp-PDT elicited ICD on T-cell immunity. Autophagy-competent or autophagy-ablated A375m cancer cells were treated with Hyp-PDT and these were fed to the hu-iDCs for 24 h. Subsequently, these pulsed DCs were exposed to T cells followed by analysis of activation based on their increased proliferation.…”

“…Rapid and extensive proliferation of T cells following encounter with 'danger' or antigenic stimulation (along with proper costimulation) 27 is one of the keystone functions of adaptive immunity. 28 This property is important for antitumor immunity 29 or tumor immunogenicity 30 such that inhibition of T cell proliferation causes tumoral immune resistance. 31 Interestingly, IFNG-production from T cells, which is crucial for the immunogenicity of cancer cells, 11,13 has been shown recently to be strongly reduced when autophagy was ablated in cancer cells undergoing ICD.…”

Analogue peptides for the immunotherapy of human acute myeloid leukemia

“…Dendritic cells may also offer a powerful vehicle to present modified peptides to the immune system in AML patients [99]. Combination therapies which include chemotherapy to reduce tumor load and immunotherapy to remove MRD are expected to be superseded by conventional therapies used in conjunction with combination-immunotherapy protocols including the vaccination of patients with peptides following adoptive T-cell transfer [100] to remove residual disease.…”

Selective Activation of Oxygen-Deprived Tumor-Infiltrating Lymphocytes through Local Intratumoral Delivery of CD137 Monoclonal Antibodies

“…cancerdiscovery.aacrjournals.org Downloaded from T cells. If one knows the specifi city of these tumor-specifi c T cells, their activity can be further promoted by specifi c synthetic vaccines, again delivered locally, and by low-dose administration of interleukin (IL)-2 or IL-15 (10). Some degree of systemic immunomodulation may still be necessary to create a favorable microenvironment for T-cell entry into tumors that do not naturally allow optimal T-cell access.…”