Engineering autologous tumor cell vaccine to locally mobilize antitumor immunity in tumor surgical bed.
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ABSTRACT:
SUBMITTER: Fang L
PROVIDER: S-EPMC7304971 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The inadequate activation of antigen-presenting cells, the entanglement of T cells, and the highly immunosuppressive conditions in the tumor microenvironment (TME) are important factors that limit the effect of cancer vaccines. Studies have shown that individualized and broad antigens can fully activate anti-tumor immunity and inhibiting the function of TGF-β can facilitate T cell migration to tumor sites. Based on our previous study, we introduced a new vaccine strategy by engineering irradiated tumor cell-derived microparticles (RT-MPs), which have both individualized and broad antigens, to induce broad antitumor effects and cause immunogenic death. Encouraged by the proinflammatory effects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the high affinity between TGF-βR2 and TGF-β, we developed RT-MPs with the SARS-CoV-2 spike protein and TGF-βR2. We found that this spike protein and high TGF-βR2 expression induces the innate immune response and ameliorates the immunosuppressive TME, thereby promoting T cell activation and infiltration, and ultimately inhibiting tumor growth. In addition, when combined with anti-programmed death 1 (anti-PD-1) the engineered RT-MPs were able to generate an immune memory response and eliminate subcutaneous tumors. Our study provides a novel strategy for producing an effective personalized anti-tumor vaccine for clinical application.
2023-10-27 | GSE239631 | GEO
Project description:The inadequate activation of antigen-presenting cells, the entanglement of T cells, and the highly immunosuppressive conditions in the tumor microenvironment (TME) are important factors that limit the effect of cancer vaccines. Studies have shown that individualized and broad antigens can fully activate anti-tumor immunity and inhibiting the function of TGF-β can facilitate T cell migration to tumor sites. Based on our previous study, we introduced a new vaccine strategy by engineering irradiated tumor cell-derived microparticles (RT-MPs), which have both individualized and broad antigens, to induce broad antitumor effects and cause immunogenic death. Encouraged by the proinflammatory effects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the high affinity between TGF-βR2 and TGF-β, we developed RT-MPs with the SARS-CoV-2 spike protein and TGF-βR2. We found that this spike protein and high TGF-βR2 expression induces the innate immune response and ameliorates the immunosuppressive TME, thereby promoting T cell activation and infiltration, and ultimately inhibiting tumor growth. In addition, when combined with anti-programmed death 1 (anti-PD-1) the engineered RT-MPs were able to generate an immune memory response and eliminate subcutaneous tumors. Our study provides a novel strategy for producing an effective personalized anti-tumor vaccine for clinical application.
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Project description:Autologous cancer cell vaccines represent a multivalent patient-specific treatment. Studies have demonstrated that these immunotherapies should be combined with immunomodulators to improve results. We tested in breast cancer the antitumor effects of a 200 µg autologous tumor cells homogenate combined with 0.0625 mg of bacillus Calmette-Guérin (BCG), and 0.02% formalin. We used a 4T1 murine model of BALB/c receiving four weekly injections of either this vaccine or control treatments. The control treatments were either Phosphate Buffer Saline, BCG treated with formalin, or the tumor cells homogenate plus BCG alone. We found that mice treated with the vaccine had the lowest tumor growth rate and mitosis percentage. The vaccinated group also showed a marked increase in infiltration of antitumor cells (natural killer, CD8 + T and CD4+ Th1 cells), as well as a decrease of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Additionally, we also observed a possible activation of the immune memory response as indicated by plasma cell tumor infiltration. Our results demonstrate that our proposed breast cancer vaccine induces a potent antitumor effect in 4T1 tumor-bearing mice. Its effectiveness, low cost and simple preparation method, makes it a promising treatment candidate for personalized breast cancer immunotherapy.
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Project description:Uric acid (UA) released from dying cells has been recognized by the immune system as a danger signal. In response to UA, dendritic cells (DC) in the immune system mature and enhance the T cell response to foreign antigens. It is conceivable that the antitumor immunity of a tumor vaccine could be promoted by the administration of UA. To test this concept, we applied UA as an adjuvant to a DC-based vaccine, and discovered that the administration of UA as an adjuvant significantly enhanced the ability of the tumor lysate-pulsed DC vaccine in delaying the tumor growth. The antitumor activity was achieved with adoptively transferred lymphocytes, and both CD8(+) T cells and NK cells were required to achieve effective immunity. This resulted in an increased accumulation of activated CD8(+) T cells and an elevated production of IFN-γ. Collectively, our study shows that the administration of UA enhances the antitumor activity of tumor lysate-pulsed DC vaccine, thus providing the preclinical rationale for the application of UA in DC-based vaccine strategies.
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Project description:Whole tumor lysates are promising antigen sources for dendritic cell (DC) therapy as they contain many relevant immunogenic epitopes to help prevent tumor escape. Two common methods of tumor lysate preparations are freeze-thaw processing and UVB irradiation to induce necrosis and apoptosis, respectively. Hypochlorous acid (HOCl) oxidation is a new method for inducing primary necrosis and enhancing the immunogenicity of tumor cells.We compared the ability of DCs to engulf three different tumor lysate preparations, produce T-helper 1 (TH1)-priming cytokines and chemokines, stimulate mixed leukocyte reactions (MLR), and finally elicit T-cell responses capable of controlling tumor growth in vivo.We showed that DCs engulfed HOCl-oxidized lysate most efficiently stimulated robust MLRs, and elicited strong tumor-specific IFN-? secretions in autologous T cells. These DCs produced the highest levels of TH1-priming cytokines and chemokines, including interleukin (IL)-12. Mice vaccinated with HOCl-oxidized ID8-ova lysate-pulsed DCs developed T-cell responses that effectively controlled tumor growth. Safety, immunogenicity of autologous DCs pulsed with HOCl-oxidized autologous tumor lysate (OCDC vaccine), clinical efficacy, and progression-free survival (PFS) were evaluated in a pilot study of five subjects with recurrent ovarian cancer. OCDC vaccination produced few grade 1 toxicities and elicited potent T-cell responses against known ovarian tumor antigens. Circulating regulatory T cells and serum IL-10 were also reduced. Two subjects experienced durable PFS of 24 months or more after OCDC.This is the first study showing the potential efficacy of a DC vaccine pulsed with HOCl-oxidized tumor lysate, a novel approach in preparing DC vaccine that is potentially applicable to many cancers.
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Project description:Here, we report on the results of a phase I/II trial (NCT00490529) for patients with mantle cell lymphoma who, having achieved remission after immunochemotherapy, were vaccinated with irradiated, CpG-activated tumor cells. Subsequently, vaccine-primed lymphocytes were collected and reinfused after a standard autologous stem cell transplantation (ASCT). The primary endpoint was detection of minimal residual disease (MRD) within 1 yr after ASCT at the previously validated threshold of ?1 malignant cell per 10,000 leukocyte equivalents. Of 45 evaluable patients, 40 (89%) were found to be MRD negative, and the MRD-positive patients experienced early subsequent relapse. The vaccination induced antitumor CD8 T cell immune responses in 40% of patients, and these were associated with favorable clinical outcomes. Patients with high tumor PD-L1 expression after in vitro exposure to CpG had inferior outcomes. Vaccination with CpG-stimulated autologous tumor cells followed by the adoptive transfer of vaccine-primed lymphocytes after ASCT is feasible and safe.
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Project description:Metastatic colorectal cancer (CRC) is poorly immunogenic, with limited neoantigens that can be targeted by cancer vaccine. Previous approaches to upregulate neoantigen have had limited success. In this study, we investigated the role of a DNA methyltransferase inhibitor (DNMTi), 5-aza-2'-deoxycytidine (DAC), in inducing cancer testis antigen (CTA) expression and evaluated the antitumor efficacy of a combinatorial approach with an epigenetically regulated cancer vaccine EpiGVAX and DAC. A murine model of metastatic CRC treated with combination therapy with an irradiated whole-cell CRC vaccine (GVAX) and DAC was used to assess the antitumor efficacy. DAC significantly induced expression of CTAs in CRC, including a new CTA Tra-P1A with a known neoepitope, P1A. Epigenetically modified EpiGVAX with DAC improved survival outcomes of GVAX. Using the epigenetically regulated antigen Tra-P1A as an example, our study suggests that the improved efficacy of EpiGVAX with DAC may due in part to the enhanced antigen-specific antitumor immune responses. This study shows that epigenetic therapy with DNMTi can not only induce new CTA expression but may also sensitize tumor cells for immunotherapy. Neoantigen-based EpiGVAX combined with DAC can improve the antitumor efficacy of GVAX by inducing antigen-specific antitumor T cell responses to epigenetically regulated proteins.
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