Brain Cancer SPORE Research Projects

In order to improve the poor outcomes in glioma patients, we previously developed a replication-competent, tumor-selective oncolytic adenovirus, Delta-24-RGD (DNX2401). This virus was tested in a first-in-human Phase I clinical trial in patients with recurrent malignant gliomas (NCT00805376), in which complete and durable responses were observed in a subset of patients. The data from this clinical trial demonstrated that Delta-24-RGD eliminated tumor cells both by direct killing of tumor cells and by inducing an anti-tumor cytotoxic T -cell immune response. These results emphasized the need to develop approaches to amplify the anti-tumor effects of Delta-24-RGD. In this project, 2 convergent approaches will be used to achieve this goal. The first approach combines the use of an immune checkpoint inhibitor, pembrolizumab, with Delta-24-RGD and the second approach will develop and test next generation Delta-24-RGD viruses that are “armed” with immune costimulatory molecules which activate immune responses. 

Specific Aim 1: To test the combination of Delta-24-RGD with anti-PD-1 antibodies in patients with recurrent malignant gliomas.

Specific Aim 2: Assess the safety and biological effects of a next-generation Delta-24-RGD expressing OX40L in patients with recurrent glioma.

Specific Aim 3: To characterize the anti-glioma effect elicited by additional next generation Delta-24-RGD viruses, including Delta-24-RGDOX, Delta-24-GREAT, Delta-24-ACT and their combinations.

Recent Publications:

Laspidea V, Puigdelloses M, Labiano S, Marrodán L, Garcia-Moure M, Zalacain M, Gonzalez-Huarriz M, Martínez-Vélez N, Ausejo-Mauleon I, de la Nava D, Herrador-Cañete G, Marco-Sanz J, Guruceaga E, de Andrea CE, Villalba M, Becher O, Squatrito M, Matía V, Gállego Pérez-Larraya J, Patiño-García A, Gupta S, Gomez-Manzano C, Fueyo J, Alonso MM. Exploiting 4-1BB immune checkpoint to enhance the efficacy of oncolytic virotherapy for diffuse intrinsic pontine gliomas. JCI Insight. 2022 Apr 8;7(7). doi: 10.1172/jci.insight.154812. PubMed PMID: 35393952; PubMed Central PMCID: PMC9057625.

Phillips LM, Li S, Gumin J, Daou M, Ledbetter D, Yang J, Singh S, Parker Kerrigan BC, Hossain A, Yuan Y, Gomez-Manzano C, Fueyo J, Lang FF. An immune-competent, replication-permissive Syrian Hamster glioma model for evaluating Delta-24-RGD oncolytic adenovirus. Neuro Oncol. 2021 Nov 2;23(11):1911-1921. doi: 10.1093/neuonc/noab128. PubMed PMID: 34059921; PubMed Central PMCID: PMC8563315.

Rivera-Molina Y, Jiang H, Fueyo J, Nguyen T, Shin DH, Youssef G, Fan X, Gumin J, Alonso MM, Phadnis S, Lang FF, Gomez-Manzano C. GITRL-armed Delta-24-RGD oncolytic adenovirus prolongs survival and induces anti-glioma immune memory. Neurooncol Adv. 2019 May-Dec;1(1):vdz009. doi: 10.1093/noajnl/vdz009. Epub 2019 Jun 5. PubMed PMID: 31608328; PubMed Central PMCID: PMC6777503.

Gállego Pérez-Larraya J, Garcia-Moure M, Labiano S, Patiño-García A, Dobbs J, Gonzalez-Huarriz M, Zalacain M, Marrodan L, Martinez-Velez N, Puigdelloses M, Laspidea V, Astigarraga I, Lopez-Ibor B, Cruz O, Oscoz Lizarbe M, Hervas-Stubbs S, Alkorta-Aranburu G, Tamayo I, Tavira B, Hernandez-Alcoceba R, Jones C, Dharmadhikari G, Ruiz-Moreno C, Stunnenberg H, Hulleman E, van der Lugt J, Idoate MÁ, Diez-Valle R, Esparragosa Vázquez I, Villalba M, de Andrea C, Núñez-Córdoba JM, Ewald B, Robbins J, Fueyo J, Gomez-Manzano C, Lang FF, Tejada S, Alonso MM. Oncolytic DNX-2401 Virus for Pediatric Diffuse Intrinsic Pontine Glioma. N Engl J Med. 2022 Jun 30;386(26):2471-2481. doi: 10.1056/NEJMoa2202028. PMID: 35767439.

In this project, the safety and effectiveness of natural killer (NK) cells as an anti-glioblastoma (GBM) therapeutic will be evaluated. The use of an allogeneic “off-the-shelf” cord blood (CB) product as the source of NK cells for cell therapy eliminates the logistical complications of autologous T cells, including poor function, which may contribute to the failure of CAR-T cell-based therapies in glioblastoma (GBM).  We have previously shown that NK cells are highly cytotoxic against GBM cancer stem cell lines and are one of the most abundant immune subsets infiltrating GBM. However, NK cells become irreversibly, immunologically unresponsive due to TGF-β that is secreted by GBM cells. To circumvent immune suppression by GBM cells and by corticosteroid therapy, we have developed NK cells in which the TGF-β receptor 2 (TGF-βR2) and the glucocorticoid receptor (NR3C1) are no longer expressed. These newly-created double knockout (TGF-βR2 and NR3C1) CB-NK cells are resistant to immunosuppressive effects and exert efficient in vitro and in vivo killing of GBM cancer stem cells. We have also developed CB-NK cells armed with cytokines, specifically IL-12, IL-15 and IL-21, based on the idea that the introduction of a cytokine gene will enhance in vivo persistence and potency of NK cells. 

Specific Aim 1:  To initiate a Phase 1/II study the safety and efficacy of TGF-βR2-/NR3C1-CB-NK cells in relapsed/recurrent GBM.

Specific Aim 2: Study the fate of TGF-βR2-/NR3C1-CB-NK cells and associated immune changes in the CNS and correlate the findings with disease response.  

Specific Aim 3: Determine if the membrane-anchored IL-12, IL-21 or IL-15 can further increase the persistence and potency of TGF-βR2-/NR3C1-CB-NK cells against GBM without undue toxicity.

Recent Publications:

Shaim H, Shanley M, Basar R, Daher M, Gumin J, Zamler DB, Uprety N, Wang F, Huang Y, Gabrusiewicz K, Miao Q, Dou J, Alsuliman A, Kerbauy LN, Acharya S, Mohanty V, Mendt M, Li S, Lu J, Wei J, Fowlkes NW, Gokdemir E, Ensley EL, Kaplan M, Kassab C, Li L, Ozcan G, Banerjee PP, Shen Y, Gilbert AL, Jones CM, Bdiwi M, Nunez-Cortes AK, Liu E, Yu J, Imahashi N, Muniz-Feliciano L, Li Y, Hu J, Draetta G, Marin D, Yu D, Mielke S, Eyrich M, Champlin RE, Chen K, Lang FF, Shpall EJ, Heimberger AB, Rezvani K. Targeting the αv integrin/TGF-β axis improves natural killer cell function against glioblastoma stem cells. J Clin Invest. 2021 Jul 15;131(14). doi: 10.1172/JCI142116. PubMed PMID: 34138753; PubMed Central PMCID: PMC8279586.

Recent advances in cancer genomics have provided a significant amount of information regarding the molecular landscape in malignant gliomas. However, most of the sample sets employed in these groundbreaking studies were derived from White or East Asian patients. Very little is currently known about the somatic and germline landscapes of gliomas in Black or Hispanic populations. There are significant differences in the annual incidence and clinical performance of gliomas in these minorities relative to those of Whites, which suggests that fundamental and clinically-relevant genetic distinctions exist between the groups. We recently found that patterns of germline single nucleotide polymorphisms (SNPs) are differentially associated with the risk of glioma by ethnic group and that the risk of glioma development in Blacks and Hispanics differs based on the level of their White ancestry. We also identified a unique set of SNPs that appear to confer glioma susceptibility in Blacks and Hispanics. These findings indicate that a larger study, probing both somatic and germline molecular profiles exclusively in Black and Hispanic patients, would bridge crucial knowledge gaps, setting the stage for more optimized, individualized patient management. 

Specific Aim 1: Characterize the somatic genomic landscape of gliomas in Black and Hispanic patients.

Specific Aim 2: Determine the extent to which racial and ethnic composition in Blacks and Hispanics correlates with disease-defining molecular alterations.

Specific Aim 3: Evaluate the extent to which germline and the somatic variation in Blacks and Hispanics impact clinical outcomes.

Recent Publications:

Ostrom QT, Egan KM, Nabors LB, Gerke T, Thompson RC, Olson JJ, LaRocca R, Chowdhary S, Eckel-Passow JE, Armstrong G, Wiencke JK, Bernstein JL, Claus EB, Il'yasova D, Johansen C, Lachance DH, Lai RK, Merrell RT, Olson SH, Sadetzki S, Schildkraut JM, Shete S, Houlston RS, Jenkins RB, Wrensch MR, Melin B, Amos CI, Huse JT, Barnholtz-Sloan JS, Bondy ML. Glioma risk associated with the extent of estimated European genetic ancestry in African Americans and Hispanics. Int J Cancer. 2020 Feb 1;146(3):739-748. doi: 10.1002/ijc.32318. Epub 2019 Apr 22. PubMed PMID: 30963577; PubMed Central PMCID: PMC6785354.

Core A: Administrative Core

Co-Directors: Frederick Lang, M.D., and Juan Fueyo, M.D.
SPORE Administrator: Biny Joseph, Ph.D.

Purpose: To provide a highly effective and centralized administration for the overall management of the Core in relation to scientific, administrative, financial and interactive aims.

Core B: Pathology and Biorepository Core

Co-Directors: Jason Huse, M.D., Ph.D., and Frederick Lang, M.D.

Purpose: Collects, processes, and maintains human tissue specimens from patients, and disperses these tissues to SPORE investigators.

Core C: Biostatistics and Bioinformatics Core

Co-Directors: Ying Yuan, Ph.D.

Purpose: To support the clinical and laboratory-based projects of the SPORE grant so that research studies are efficiently designed, conducted, monitored and analyzed.

Core D: Animal Core 

Co-Directors: Betty Kim, M.D., Ph.D., and Sherise Ferguson, M.D.

Purpose: To provide support for animal models.