Granzyme B PET Imaging in Response to In Situ Vaccine Therapy Combined with αPD1 in a Murine Colon Cancer Model

Immune checkpoint inhibitors (ICIs) block checkpoint receptors that tumours use for immune evasion, allowing immune cells to target and destroy cancer cells. Despite rapid advancements in immunotherapy, durable response rates to ICIs remains low. To address this, combination clinical trials are underway assessing whether adjuvants can enhance responsiveness by increasing tumour immunogenicity. CpG-oligodeoxynucleotides (CpG-ODN) are synthetic DNA fragments containing an unmethylated cysteine-guanosine motif that stimulate the innate and adaptive immune systems by engaging Toll-like receptor 9 (TLR9) present on the plasmacytoid dendritic cells (pDCs) and B cells. Here, we have assessed the ability of AlF-mNOTA-GZP, a peptide tracer targeting granzyme B, to serve as a PET imaging biomarker in response to CpG-ODN 1585 in situ vaccine therapy delivered intratumourally (IT) or intraperitoneally (IP) either as monotherapy or in combination with αPD1. [18F]AlF-mNOTA-GZP was able to differentiate treatment responders from non-responders based on tumour uptake. Furthermore, [18F]AlF-mNOTA-GZP showed positive associations with changes in tumour-associated lymphocytes expressing GZB, namely GZB+ CD8+ T cells, and decreases in suppressive F4/80+ cells. [18F]AlF-mNOTA-GZP tumour uptake was mediated by GZB expressing CD8+ cells and successfully stratifies therapy responders from non-responders, potentially acting as a non-invasive biomarker for ICIs and combination therapy evaluation in a clinical setting.

NIMG-59. RADIOMICS-PREDICTED T CELL DYNAMICS STRATIFY SURVIVAL AFTER DENDRITIC CELL VACCINE THERAPY FOR PRIMARY GLIOBLASTOMA

INTRODUCTION Dendritic cells (DCs) are potent antigen presenting cells that can be exploited to initiate an adaptive anti-tumoral immune response. DC vaccine clinical trials for primary glioblastoma (GBM) have reported prolonged progression-free survival without any impact on overall survival (OS). We report a radiomics approach that identifies a subpopulation of patients with prolonged OS in clinical trial MC1272. METHODS Twenty adults with primary GBM undergoing standard-of-care therapy were enrolled in MC1272. Autologous DCs were pulsed with allogenic GBM cell lines to generate vaccines that were administered for up to twelve cycles. Standard brain imaging was obtained at the initiation of treatment and two months afterwards. An independent cohort of image-localized biopsies underwent RNA sequencing followed by cellular deconvolution to estimate T cell abundance. A machine learning model was trained to predict intratumoral T cell abundance from imaging features, and the model was applied to MC1272 patient imaging. RESULTS Voxelwise predictions of T cell abundance were generated for each patient’s pre- and post-treatment images. The difference in total intratumoral T cell abundance between imaging timepoints classified patients into increasing or decreasing T cell groups. Patients whose T cells increased had longer OS (median, 21 months) than those whose T cells decreased (median, 10 months; p=0.0035). The significance remained in a Cox proportional hazards analysis that adjusted for patient age and sex (p=0.011). CONCLUSIONS A spatially-resolved radiomics model detected that an intratumoral T cell influx after DC vaccine therapy was associated with prolonged OS. The “post-treatment” imaging in this study was obtained a mere two months after DC vaccine initiation, suggesting that our radiomics model can provide an early indication of treatment responsiveness and prognosis in these patients.

Tumor RNA-Transfected Dendritic Cells Generated From Induced Pluripotent Stem Cells Induces Anti-Tumor Immunity

Significant efficacy of induced pluripotent stem cells (iPSCs) in generating DCs for cancer vaccine therapy was suggested in our previous studies. In clinical application of DC vaccine therapy, however, few DC vaccine systems have shown strong clinical response. To enhance immunogenicity in the DC vaccine, we transfected patient-derived iPSDCs with in vitro transcriptional RNA (ivtRNA), which was obtained from tumors of three patients with colorectal cancer.We investigated iPSDCs-ivtRNA which were induced by transfecting ivtRNA obtained from tumors of three colorectal cancer patients, and examined its antitumor effect. Moreover, we analyzed neoantigens expressed in colorectal cancer cells and examined whether iPSDCs-ivtRNA induced cytotoxic T lymphocytes (CTLs) against the predicted neoantigens.CTLs activated by iPSDCs-ivtRNA exhibited cytotoxic activity against the tumor spheroids in all three patients with colorectal cancer. Whole-exome sequencing revealed 1251 nonsynonymous mutations and 2155 neoantigens (IC50 <500 nM) were predicted. For IFN-γ ELISPOT assay, these candidate neoantigens were further prioritised and 12 candidates were synthesized. IFN-γ ELISPOT assay revealed that the CTLs induced by iPSDCs-ivtRNA responded to one of the candidate neoantigens.In vitro CTLs obtained by transfecting tumor-derived RNA into iPSDCs derived from three patients with colorectal cancer showed potent tumor-specific killing effect.

Vaccine diagnosis and vaccine therapy of ascending gonorrhea in women. Weinzierl (Zeit f. Geb., Bd. 84),

Weinzierl (Zeit. F. Geb., Bd. 84), using vaccination with artigon Vrusk'a (polyvalent vaccine prepared from 20 different generations of gonococci and containing 20 million killed microbes in 1 cubic sant.) In 96 patients with inflammatory tumors uterine appendages, and artigon was injected intravenously

Current state of the art of protein therapy

The subject of my lecture is the doctrine of the nonspecific treatment of infectious and other diseases, which, under the name Proteinkrpertherapie, currently combines a number of long-known therapeutic methods, such as: vaccine therapy, serotherapy, organotherapy, as well as those departments of pharmacotherapy where the current principles are various substances of a protein nature.

Prof. Zlatogorov, etc.-Assoc. Lavrinovich. Vaccine therapy and protein therapy. Ed. 2nd. Kharkov. 1923.

Already the first edition of this book, published under the title "Vaccine Therapy in Medicine" more than 8 years ago as an appendix to "Doctor. Gazeta , aroused interest not only among practitioners, but also among theoretical bacteriologists. The burning question of vaccine therapy in Zap. Europe and America have received a lot of attention before, but recently, due to the fact that protein treatment began to spread widely abroad, many issues of vaccine therapy have received completely different coverage.

Multiple sclerosis vaccine therapy

Steiner reports to the Zentr. f. d. ges Neurol, und Psych., Bd XXXIV, 1923, on his observations of the vaccine therapy proposed by Grossem for multiple sclerosis.