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Last Updated: 04/29/22

2021 SPORE Advances

[+] Brain

Maciej S. Lesniak, MD - Northwestern University Brain Cancer SPORE

A first-in-human phase 0 clinical study of RNA interference-based spherical nucleic acids in patients with recurrent glioblastoma

This study is a single-arm, open-label phase 0 first-in-human trial to determine the safety, pharmacokinetics, intratumoral accumulation and gene-suppressive activity of systemically administered, brain-penetrant spherical nucleic acids (SNAs) carrying siRNA specific for the GBM oncogene Bcl2Like12 (Bcl2L12). Patients with recurrent GBM were treated with intravenous administration of siBcl2L12-SNAs, called NU-0129, followed by tumor resection. Safety assessment revealed no grade 4 or 5 treatment-related toxicities. Results in resected GBM tissue demonstrated that SNAs reached patient tumors, with gold enrichment observed in the tumor-associated endothelium, macrophages, and tumor cells. NU-0129 uptake into glioma cells correlated with a reduction in tumor-associated Bcl2L12 protein expression. These results establish SNA nanoconjugates as a potential brain-penetrant precision medicine approach for the systemic treatment of GBM.

Citation:
Kumthekar P, Ko CH, Paunesku T, Dixit K, Sonabend AM, Bloch O, Tate M, Schwartz M, Zuckerman L, Lezon R, Lukas RV, Jovanovic B, McCortney K, Colman H, Chen S, Lai B, Antipova O, Deng J, Li L, Tommasini-Ghelfi S, Hurley LA, Unruh D, Sharma NV, Kandpal M, Kouri FM, Davuluri RV, Brat DJ, Muzzio M, Glass M, Vijayakumar V, Heidel J, Giles FJ, Adams AK, James CD, Woloschak GE, Horbinski C, Stegh AH. A first-in-human phase 0 clinical study of RNA interference-based spherical nucleic acids in patients with recurrent glioblastoma. Sci Transl Med. 2021 Mar 10;13(584):eabb3945. doi: 10.1126/scitranslmed.abb3945. PMCID: PMC8272521. PMID: 33692132

[+] Breast

Charles Perou, PhD, H. Shelton Earp III, MD, & Lisa Carey, MD University of North Carolina SPORE in Breast Cancer

Outcomes of Hormone-Receptor Positive, HER2-Negative Breast Cancers by Race and Tumor Biological Features

Black women with clinically favorable HR+/HER2 tumors had statistically significantly higher risk of recurrence relative to White women (crude HR ¼ 1.81, 95% CI ¼ 1.34 to 2.46), even after adjusting for age, grade, node status, and tumor size (standardized HR ¼ 1.42, 95% CI ¼ 1.05 to 1.93). Overall, higher risk of recurrence among Black women was reduced but not eliminated after adjusting for baseline tumor characteristics. Disparities in recurrence patterns were most striking in high-risk subgroups of HR+/HER2 patients, notably those with a high ROR-PT score and high grade. These high-risk women may be most in need of appropriate treatment, and therefore treatment differences identified in Black vs White women (treatment delay and lower endocrine therapy initiation) are important targets to close these recurrence gaps.

Citation:
Benefield HC, Reeder-Hayes KE, Nichols HB, Calhoun BC, Love MI, Kirk EL, Geradts J, Hoadley KA, Cole SR, Earp HS, Olshan AF, Carey LA, Perou CM, Troester MA. Outcomes of Hormone-Receptor Positive, HER2-Negative Breast Cancers by Race and Tumor Biological Features. JNCI Cancer Spectr. 2020 Sep 23;5(1):pkaa072. doi: 10.1093/jncics/pkaa072. PMCID: PMC7791616. PMID: 33442657

[+] Hyperactive RAS

D. Wade Clapp, MD, & Kevin Shannon, MD - Indiana University Hyperactive Ras Tumor SPORE

Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial

This study describes a phase II, open-label, nonrandomized clinical trial to assess the safety, efficacy and biological activity of cabozantinib in patients ?16 years of age with neurofibromatosis type 1 (NF1) and progressive or symptomatic, inoperable plexiform neurofibroma (PN). Eight of 19 evaluable trial participants (42%) achieved a partial response and no patients had disease progression while on treatment. The data indicate that cabozantinib is active in NF1-associated PN, resulting in tumor volume reduction and pain improvement.

Citation:
Fisher MJ, Shih CS, Rhodes SD, Armstrong AE, Wolters PL, Dombi E, Zhang C, Angus SP, Johnson GL, Packer RJ, Allen JC, Ullrich NJ, Goldman S, Gutmann DH, Plotkin SR, Rosser T, Robertson KA, Widemann BC, Smith AE, Bessler WK, He Y, Park SJ, Mund JA, Jiang L, Bijangi-Vishehsaraei K, Robinson CT, Cutter GR, Korf BR; Neurofibromatosis Clinical Trials Consortium, Blakeley JO, Clapp DW. Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial. Nat Med. 2021 Jan;27(1):165-173. doi: 10.1038/s41591-020-01193-6. Epub 2021 Jan 13. PMCID: PMC8275010. PMID: 33442015

[+] Leukemia, Lymphoma

David F. McDermott, MD, & William G. Kaelin, Jr., MD - Beth Israel Deaconess Medical Center/Dana-Farber/Harvard Cancer Center Kidney Cancer SPORE

KIR3DL3 Is an Inhibitory Receptor for HHLA2 that Mediates an Alternative Immunoinhibitory Pathway to PD1

HERV-H LTR-associating 2 (HHLA2; also known as B7H5 and B7H7), a member of the B7 family of immunoregulatory ligands that mediates costimulatory effects through its interaction with the CD28 family member transmembrane and immunoglobulin domain containing 2 (TMIGD2) has been known to have inhibitory effects on T cells. This paper reports killer cell immunoglobulin-like receptor, three immunoglobulin domains and long cytoplasmic tail 3 (KIR3DL3) as an inhibitory receptor for HHLA2 in T cells and natural killer (NK) cells. Investigators generated HHLA2 and KIR3DL3 antibodies that block the immune-inhibitory activity of HHLA2, preserving the costimulatory signal. Blockade of both the PD1 and KIR3DL3 pathways may be a more effective way to reverse tumor immune evasion.

Citation:
Bhatt RS, Berjis A, Konge JC, Mahoney KM, Klee AN, Freeman SS, Chen CH, Jegede OA, Catalano PJ, Pignon JC, Sticco-Ivins M, Zhu B, Hua P, Soden J, Zhu J, McDermott DF, Arulanandam AR, Signoretti S, Freeman GJ. KIR3DL3 Is an Inhibitory Receptor for HHLA2 that Mediates an Alternative Immunoinhibitory Pathway to PD1. Cancer Immunol Res. 2021 Feb;9(2):156-169. doi: 10.1158/2326-6066.CIR-20-0315. Epub 2020 Nov 23. PMCID: PMC8284010. PMID: 33229411

Marina Konopleva, MD, PhD, & Elizabeth Shpall, MD - The University of Texas MD Anderson Cancer Center Leukemia SPORE

Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors

Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is remarkably effective in B-cell cancers. However, CAR T cells may induce toxicity and are difficult to produce. In this phase 1/2 trial HLA-mismatched anti CD19 CAR-Natural Killer (NK) cells were administered to 11 patients with relapsed or refractory CD19-positive cancers (non-Hodgkin's lymphoma or chronic lymphocytic leukemia [CLL]). Eight patients (73%) had a response; of these patients, 7 (4 with lymphoma and 3 with CLL) had a complete remission, and 1 had remission of the Richter's transformation component but had persistent CLL.

Citation:
Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, Nassif Kerbauy L, Overman B, Thall P, Kaplan M, Nandivada V, Kaur I, Nunez Cortes A, Cao K, Daher M, Hosing C, Cohen EN, Kebriaei P, Mehta R, Neelapu S, Nieto Y, Wang M, Wierda W, Keating M, Champlin R, Shpall EJ, Rezvani K. Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors. N Engl J Med. 2020 Feb 6;382(6):545-553. doi: 10.1056/NEJMoa1910607. PMCID: PMC7101242. PMID: 32023374

[+] Lung

Charles Rudin, MD, PhD - Coordinating center for the NCI small cell lung cancer research consortium

MYC Drives Temporal Evolution of Small Cell Lung Cancer Subtypes by Reprogramming Neuroendocrine Fate

Using mouse and human models with a time-series single-cell transcriptome analysis the paper reveals that MYC drives dynamic evolution of SCLC subtypes. In neuroendocrine cells, MYC activates Notch to dedifferentiate tumor cells, promoting a temporal shift in SCLC from ASCL1+ to NEUROD1+ to YAP1+ states. MYC alternatively promotes POU2F3+ tumors from a distinct cell type.

Citation:
Ireland AS, Micinski AM, Kastner DW, Guo B, Wait SJ, Spainhower KB, Conley CC, Chen OS, Guthrie MR, Soltero D, Qiao Y, Huang X, Tarapcsák S, Devarakonda S, Chalishazar MD, Gertz J, Moser JC, Marth G, Puri S, Witt BL, Spike BT, Oliver TG. MYC Drives Temporal Evolution of Small Cell Lung Cancer Subtypes by Reprogramming Neuroendocrine Fate. Cancer Cell. 2020 Jul 13;38(1):60-78.e12. doi: 10.1016/j.ccell.2020.05.001. Epub 2020 May 30. PMCID: PMC7393942. PMID: 32473656

[+] Myeloma

Kenneth Anderson, MD, & Nikhil Munshi, MD - Dana-Farber/Harvard Cancer Center Multiple Myeloma SPORE

Genome-Wide Somatic Alterations in Multiple Myeloma Reveal a Superior Outcome Group

The overall goal of this study was to describe the genomic landscape of myeloma using deep whole-genome sequencing (WGS) and develop a model that identifies patients with long survival. The investigators identified a genomically defined MM subgroup (17% of newly diagnosed patients) with low DNA damage (low genomic scar score with chromosome 9 gain) and a superior outcome (100% overall survival at 69 months), which was validated in a large independent cohort. Surprisingly, patients' overall survival was independent of International Staging System and minimal residual disease status. Identification of this patient subgroup will affect future therapeutic algorithms and research planning.

Citation:
Samur MK, Aktas Samur A, Fulciniti M, Szalat R, Han T, Shammas M, Richardson P, Magrangeas F, Minvielle S, Corre J, Moreau P, Thakurta A, Anderson KC, Parmigiani G, Avet-Loiseau H, Munshi NC. Genome-Wide Somatic Alterations in Multiple Myeloma Reveal a Superior Outcome Group. J Clin Oncol. 2020 Sep 20;38(27):3107-3118. doi: 10.1200/JCO.20.00461. Epub 2020 Jul 20. PMCID: PMC7499613. PMID: 32687451

[+] Prostate

Sarki Abdulkadir, MD, PhD, & Maha Hussain, MD, FACP, FASCO - Northwestern University Prostate Cancer SPORE

Factors Associated with Time to Conversion from Active Surveillance to Treatment for Prostate Cancer in a Multi-Institutional Cohort

This report evaluated the relationship between common and rare germline genetic variants in prostate cancer (PrCa) patients and active surveillance (AS) failure. The study analyzed a multi-institutional cohort of 6,775 patients with PrCa being managed with active surveillance at 28 medical centers. Data and biospecimens were collected for germline genetic analyses (performed by NCI-Center for Inherited Disease Research (CIDR)). Their preliminary findings found that approximately a third of patients under AS had converted to treatment with a median follow-up of 6.7 years. They found the risk of conversion was higher in the patients with high volume grade tumors, and there was no difference between black and white patients for time to conversion to treatment. Data is available on dbGaP for continued analysis.

Citation:
Cooley LF, Emeka AA, Meyers TJ, Cooper PR, Lin DW, Finelli A, Eastham JA, Logothetis CJ, Marks LS, Vesprini D, Goldenberg SL, Higano CS, Pavlovich CP, Chan JM, Morgan TM, Klein EA, Barocas DA, Loeb S, Helfand BT, Scholtens DM, Witte JS, Catalona WJ; Collaborators. Factors Associated with Time to Conversion from Active Surveillance to Treatment for Prostate Cancer in a Multi-Institutional Cohort. J Urol. 2021 Nov;206(5):1147-1156. doi: 10.1097/JU.0000000000001937. Epub 2021 Sep 10. PMCID: PMC8734323. PMID: 34503355