Basis Of Cancer Immunotherapy Research Articles

Abstract IA18: The mechanistic basis of cancer immunotherapy

Abstract The advent of new approaches to the immunotherapy of cancer has caused a dramatic shift not only in the treatment of cancer but also in our understanding of cancer biology. The rapid rate of progress in the clinic, however, has outpaced our understanding of the basic mechanistic features that underlie the therapeutic advances. This is most notable in the case of “checkpoint” inhibitors, such as antibodies to the negative regulatory axis defined by PD-1 and PD-L1. While blocking the interaction of PD-L1 with PD-1 is often assumed to reverse the process of T-cell exhaustion, there is little direct evidence for this interpretation, an incomplete definition of what is meant by “exhaustion,” and a poor understanding of how PD-1 regulates T-cell activity. Starting with observations made in the clinic, we have used biochemical reconstitution together with in vivo analysis in mice to illuminate key features of the PD-L1/PD-1 axis, demonstrating that it functions primarily to regulate T-cell function by controlling signaling by costimulators such as CD28. Conditional knockout experiments also revealed that dendritic cell B7.1 plays a uniquely important role in activating CD28. Distinct from costimulatory molecules, entirely different regulatory mechanisms appear to regulate T-cell receptor signaling. Finally, we have begun to evaluate the origin of T cells that engage antitumor responses, results that further emphasize a need for continuous priming of antitumor T cells to maintain a potent anticancer response. Citation Format: Ira Mellman. The mechanistic basis of cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr IA18.

Abstract 4695: Murine tumor growth suppression through CD8+CTLs via activated DEC-205+dendritic cells by sequential administration of α-galactosylceramide in vivo

Abstract Cancer immunotherapy is mediated by the effective priming and activation of tumor-specific class I major histocompatibility complex molecule-restricted CD8+ cytotoxic T lymphocytes. DEC-205+ dendritic cells can cross-present the epitopes of captured tumor antigens associated with class I MHC molecules alongside co-stimulatory molecules to prime and activate tumor-specific CD8+ CTLs. Immunosuppressive tolerogenic DCs with reduced co-stimulatory molecules may be a cause of insufficient CTL induction. Hepa1-6-1 cells were established from the mouse hepatoma cell line Hepa1-6; these cells grow continuously after subcutaneous implantation into syngeneic C57BL/6 mice and do not prime CD8+ CTLs. Here, we show that the growing of tumors was suppressed by activated CD8+ CTLs with tumor-specific cytotoxicity through the administration of the glycolipid α-galactosylceramide, which is a compound known to stimulate invariant natural killer T cells and selectively activate DEC-205+ DCs. Moreover, we demonstrated that sequential repetitive intraperitoneal inoculation of α-GalCer every 48 hour appeared to convert tolerogenic DEC-205+ DCs into immunogenic DCs with a higher expression of co-stimulatory molecules and a greater cross-presentation capacity, which primed CTL precursors and induced tumor-specific CD8+ CTLs within the tumor environment without activating iNKT cells. These findings provide a new basis for cancer immunotherapy to convert tolerogenic DEC-205+ DCs within tumors into immunogenic DCs via the sequential administration of an immuno-potent lipid/glycolipid, and activated immunogenic DCs expressing sufficient suitable co-stimulatory molecules will prime and activate tumor-specific CD8+ CTLs within the tumor to control tumor growing. Citation Format: Hideki Kogo, Hidemi Takahashi, Eiji Uchida. Murine tumor growth suppression through CD8+CTLs via activated DEC-205+dendritic cells by sequential administration of α-galactosylceramide in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4695.

Abstract LB-287: Combining immunomics and genomics for immunotherapy of refractory and rare cancers

Abstract Introduction: An underlying basis of cancer immunotherapy is the activation of the patient's own immune effector cells to specifically eradicate tumor cells. Different strategies of cancer immunotherapy have shown outstanding success in a number of patients across various tumor types. However, currently only a fraction of patients respond to immunotherapy, and therapy works only in a subset of tumors. To understand why, an integrated analysis of host and tumor factors is required. Fundamental issues in the analysis of key prognostic and predictive components include elucidating the complex interaction between tumors and their microenvironment, determining the type and densities of tumor-infiltrating immune cells, and understanding how the mutational load influences therapy outcome. Sophisticated analysis is required for patients with refractory or rare cancers to explore new therapeutic strategies. We established a systems medicine approach to obtain detailed data about tumor-host interactions, which may provide information on clinical outcome and help identify patients who are most likely to benefit from immunotherapy. Methods and Results: Whole-exome sequencing of tumor and control samples is performed from freshly obtained patient samples. In addition, whole-transcriptome sequencing of tumor tissue is performed if possible. Single nucleotide variations (SNVs) are detected in each tumor. Sequence-based HLA typing and computational epitope prediction methods are used to assess the immunogenicity of each SNV. The grade of immune cell infiltration and the expression of selected immunomodulatory proteins, e.g. PD-1 and PD-L1, is assessed by immunohistochemical stainings of tissue samples. Additionally, cytokine and chemokine profiles are determined in the tumor microenvironment. The resulting data can aid in treatment decision, e.g. PD-1 blocking antibodies can be administered when elevated PD-1 expression is detected. Alternatively, peptide vaccination is considered if a sufficient number of immunogenic mutations is detected. Based on the mutational profiles, mutation specific 29mer peptides and corresponding wild type peptides are produced for ELIspot assays with patient PBMCs to assess mutation-specific T cell reactivity. To assess the changes over time, blood and tissue are obtained during therapy to monitor therapy-induced changes in the periphery and the tumor microenvironment. Conclusion: Here we present our established workflow to systematically analyze tumor-host interactions in cancer patients and show preliminary data of different facets and clinical implications of these complex interactions. To evaluate and validate immunological and pathological characteristics of a tumor and the methods to assess its immunogenicity as well as its complex interplay with the microenvironment, comprehensive translational studies have to be conducted. Eventually, the obtained information will help to identify important subgroups and patients who are most likely to benefit from a certain type of immunotherapy. Citation Format: Zeynep Kosaloglu, Inka Zoernig, Niels Halama, Bruno Koehler, Anne Katrin Berger, Christoph Springfeld, Alexis Ulrich, Martin Schneider, Felix Lasitschka, Hanno Glimm, Stefan Froehling, Benedikt Brors, Dirk Jaeger. Combining immunomics and genomics for immunotherapy of refractory and rare cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-287.

Tumor-dendritic cell fusion as a basis for cancer immunotherapy

To establish the basis for use of allogeneic dendritic-tumor fusion cells. Fusion cells were created by electrofusion. We used 2 allogeneic murine tumor lines (D5 and 4T1) that were virally transduced to express the antigen (beta-galactosidase) as a surrogate tumor marker. Cross-immunization was achieved with irradiated allogenic tumor cells. Successful electrofusion of dendritic cells and tumor cells was confirmed by using fluorescence-activated cell sorting and cytospin. Significant responses were shown in immunized mice against tumor challenge and established 3-day pulmonary metastasis with fusion cells. Allogeneic tumor sharing a common tumor antigen can immunize against syngeneic tumor challenge. Fusion cells showed successful immunization against tumor challenge and showed regression of 3-day established pulmonary metastasis. These preclinical studies provide evidence that an allogenic tumor-dendritic cell fusion vaccine is a valid approach for head and neck cancer immunotherapy.

Tumor–dendritic cell fusion as a basis for cancer immunotherapy

Problem: Patients with advanced head and neck cancer are at risk for metastasis - local and regional recurrence. One approach to addressing these issues is immunotherapy. Recent studies have identified the dendritic cell (DC) as a critical component in eliciting a T-cell response against neoplastic cells. One immunotherapy approach is fusion of DCs with irradiated tumor cells by electrofusion. Methods: Fusion cells were created using electrofusion technique. We used 2 allogeneic murine tumor lines (D5 and 4T1) virally transduced to express the antigen B-galactosidase. Using beta-galactosidase as a surrogate tumor marker, we crossed immunized mice with irradiated tumor or fusion cells with subsequent tumor challenge intradermally. Fusion cells were also used in the treatment of three-day established pulmonary metastasis. Results: Cross immunization was achieved with irradiated allogenic tumor cells sharing a common antigen given subcutaneously and intranodally. Successful electrofusion of DC and tumor cells was confirmed using fluorescent activated cell sorting (FACS) and cytospin. Significant responses were demonstrated in immunized mice against tumor challenge and established 3-day pulmonary metastasis with syngeneic-fusion cells. Conclusion: Allogeneic tumors sharing a common tumor antigen can immunize against syngeneic tumor challenge. The use of syngeneic tumor-DC fusion cells demonstrated successful immunization against tumor challenge. Fusion cells also resulted in regression of 3-day established pulmonary metastasis. Significance: Difficulties are encountered in successfully and reliably generating tumor cell lines from individual patients, especially in head and neck cancer patients. Findings over recent years suggest that many tumors of the same histological origin but from different individuals may express common antigens. Therefore, a tumor from a different individual (allogeneic) may be feasible for use as a source of antigens. These preclinical studies provide evidence that an allogeneic tumor-dendritic cell fusion vaccine may be a valid approach for head and neck cancer immunotherapy. Support: American Academy of Otolaryngology-Head and Neck Surgery Resident Research Award