mRNA-based precision targeting of neoantigens and tumor-associated antigens in malignant brain tumors
Abstract Background Despite advancements in the successful use of immunotherapy in treating a variety of solid tumors, applications in treating brain tumors have lagged considerably. This is due, at least in part, to the lack of well-characterized antigens expressed within brain tumors that can medi...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Genome Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13073-024-01281-z |
| _version_ | 1797276437641691136 |
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| author | Vrunda Trivedi Changlin Yang Kelena Klippel Oleg Yegorov Christina von Roemeling Lan Hoang-Minh Graeme Fenton Elizabeth Ogando-Rivas Paul Castillo Ginger Moore Kaytora Long-James Kyle Dyson Bently Doonan Catherine Flores Duane A. Mitchell |
| author_facet | Vrunda Trivedi Changlin Yang Kelena Klippel Oleg Yegorov Christina von Roemeling Lan Hoang-Minh Graeme Fenton Elizabeth Ogando-Rivas Paul Castillo Ginger Moore Kaytora Long-James Kyle Dyson Bently Doonan Catherine Flores Duane A. Mitchell |
| author_sort | Vrunda Trivedi |
| collection | DOAJ |
| description | Abstract Background Despite advancements in the successful use of immunotherapy in treating a variety of solid tumors, applications in treating brain tumors have lagged considerably. This is due, at least in part, to the lack of well-characterized antigens expressed within brain tumors that can mediate tumor rejection; the low mutational burden of these tumors that limits the abundance of targetable neoantigens; and the immunologically “cold” tumor microenvironment that hampers the generation of sustained and productive immunologic responses. The field of mRNA-based therapeutics has experienced a boon following the universal approval of COVID-19 mRNA vaccines. mRNA-based immunotherapeutics have also garnered widespread interest for their potential to revolutionize cancer treatment. In this study, we developed a novel and scalable approach for the production of personalized mRNA-based therapeutics that target multiple tumor rejection antigens in a single therapy for the treatment of refractory brain tumors. Methods Tumor-specific neoantigens and aberrantly overexpressed tumor-associated antigens were identified for glioblastoma and medulloblastoma tumors using our cancer immunogenomics pipeline called Open Reading Frame Antigen Network (O.R.A.N). Personalized tumor antigen-specific mRNA vaccine was developed for each individual tumor model using selective gene capture and enrichment strategy. The immunogenicity and efficacy of the personalized mRNA vaccines was evaluated in combination with anti-PD-1 immune checkpoint blockade therapy or adoptive cellular therapy with ex vivo expanded tumor antigen-specific lymphocytes in highly aggressive murine GBM models. Results Our results demonstrate the effectiveness of the antigen-specific mRNA vaccines in eliciting robust anti-tumor immune responses in GBM hosts. Our findings substantiate an increase in tumor-infiltrating lymphocytes characterized by enhanced effector function, both intratumorally and systemically, after antigen-specific mRNA-directed immunotherapy, resulting in a favorable shift in the tumor microenvironment from immunologically cold to hot. Capacity to generate personalized mRNA vaccines targeting human GBM antigens was also demonstrated. Conclusions We have established a personalized and customizable mRNA-therapeutic approach that effectively targets a plurality of tumor antigens and demonstrated potent anti-tumor response in preclinical brain tumor models. This platform mRNA technology uniquely addresses the challenge of tumor heterogeneity and low antigen burden, two key deficiencies in targeting the classically immunotherapy-resistant CNS malignancies, and possibly other cold tumor types. |
| first_indexed | 2024-03-07T15:28:13Z |
| format | Article |
| id | doaj.art-dd7adebdc5ef44db8761e569a2065eb9 |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-03-07T15:28:13Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-dd7adebdc5ef44db8761e569a2065eb92024-03-05T16:37:22ZengBMCGenome Medicine1756-994X2024-01-0116111910.1186/s13073-024-01281-zmRNA-based precision targeting of neoantigens and tumor-associated antigens in malignant brain tumorsVrunda Trivedi0Changlin Yang1Kelena Klippel2Oleg Yegorov3Christina von Roemeling4Lan Hoang-Minh5Graeme Fenton6Elizabeth Ogando-Rivas7Paul Castillo8Ginger Moore9Kaytora Long-James10Kyle Dyson11Bently Doonan12Catherine Flores13Duane A. Mitchell14University of FloridaUniversity of FloridaUniversity of FloridaUniversity of FloridaUniversity of FloridaUniversity of FloridaUniversity of FloridaBoston Medical CenterUniversity of FloridaUniversity of FloridaUniversity of FloridaUniversity of FloridaUniversity of FloridaUniversity of FloridaUniversity of FloridaAbstract Background Despite advancements in the successful use of immunotherapy in treating a variety of solid tumors, applications in treating brain tumors have lagged considerably. This is due, at least in part, to the lack of well-characterized antigens expressed within brain tumors that can mediate tumor rejection; the low mutational burden of these tumors that limits the abundance of targetable neoantigens; and the immunologically “cold” tumor microenvironment that hampers the generation of sustained and productive immunologic responses. The field of mRNA-based therapeutics has experienced a boon following the universal approval of COVID-19 mRNA vaccines. mRNA-based immunotherapeutics have also garnered widespread interest for their potential to revolutionize cancer treatment. In this study, we developed a novel and scalable approach for the production of personalized mRNA-based therapeutics that target multiple tumor rejection antigens in a single therapy for the treatment of refractory brain tumors. Methods Tumor-specific neoantigens and aberrantly overexpressed tumor-associated antigens were identified for glioblastoma and medulloblastoma tumors using our cancer immunogenomics pipeline called Open Reading Frame Antigen Network (O.R.A.N). Personalized tumor antigen-specific mRNA vaccine was developed for each individual tumor model using selective gene capture and enrichment strategy. The immunogenicity and efficacy of the personalized mRNA vaccines was evaluated in combination with anti-PD-1 immune checkpoint blockade therapy or adoptive cellular therapy with ex vivo expanded tumor antigen-specific lymphocytes in highly aggressive murine GBM models. Results Our results demonstrate the effectiveness of the antigen-specific mRNA vaccines in eliciting robust anti-tumor immune responses in GBM hosts. Our findings substantiate an increase in tumor-infiltrating lymphocytes characterized by enhanced effector function, both intratumorally and systemically, after antigen-specific mRNA-directed immunotherapy, resulting in a favorable shift in the tumor microenvironment from immunologically cold to hot. Capacity to generate personalized mRNA vaccines targeting human GBM antigens was also demonstrated. Conclusions We have established a personalized and customizable mRNA-therapeutic approach that effectively targets a plurality of tumor antigens and demonstrated potent anti-tumor response in preclinical brain tumor models. This platform mRNA technology uniquely addresses the challenge of tumor heterogeneity and low antigen burden, two key deficiencies in targeting the classically immunotherapy-resistant CNS malignancies, and possibly other cold tumor types.https://doi.org/10.1186/s13073-024-01281-zPersonalized immunotherapyCancer immunitymRNA therapeuticsVaccinesAdoptive T cell therapyImmune checkpoint blockade |
| spellingShingle | Vrunda Trivedi Changlin Yang Kelena Klippel Oleg Yegorov Christina von Roemeling Lan Hoang-Minh Graeme Fenton Elizabeth Ogando-Rivas Paul Castillo Ginger Moore Kaytora Long-James Kyle Dyson Bently Doonan Catherine Flores Duane A. Mitchell mRNA-based precision targeting of neoantigens and tumor-associated antigens in malignant brain tumors Genome Medicine Personalized immunotherapy Cancer immunity mRNA therapeutics Vaccines Adoptive T cell therapy Immune checkpoint blockade |
| title | mRNA-based precision targeting of neoantigens and tumor-associated antigens in malignant brain tumors |
| title_full | mRNA-based precision targeting of neoantigens and tumor-associated antigens in malignant brain tumors |
| title_fullStr | mRNA-based precision targeting of neoantigens and tumor-associated antigens in malignant brain tumors |
| title_full_unstemmed | mRNA-based precision targeting of neoantigens and tumor-associated antigens in malignant brain tumors |
| title_short | mRNA-based precision targeting of neoantigens and tumor-associated antigens in malignant brain tumors |
| title_sort | mrna based precision targeting of neoantigens and tumor associated antigens in malignant brain tumors |
| topic | Personalized immunotherapy Cancer immunity mRNA therapeutics Vaccines Adoptive T cell therapy Immune checkpoint blockade |
| url | https://doi.org/10.1186/s13073-024-01281-z |
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