enoblituzumab (MGA271) / MacroGenics - LARVOL DELTA

Dual role of CD276 as target antigen and putative activation marker in CD276-redirected CAR T cells for the treatment of solid tumors (SITC 2024) - "Despite published CAR T cell therapies targeting CD276 (376.96, MGA271, and B12) and numerous ongoing clinical trials, the therapeutic benefits of these therapies remain underwhelming.1–3 The present study aims to develop novel, superior CAR constructs targeting human CD276 in solid tumors, and to investigate the putative role of CD276 as a T cell activating and modulatory molecule4–7 in the context of CD276-CAR-T cells...Conclusions The novel CD276-CAR-T cells CARs D0506 and D0537 maintained persistence and potent cytotoxicity upon long-term tumor cell re-challenge, concordantly with heightened CD276 surface expression during manufacturing and target-dependent activation. These findings point to CD276 as a putative activation marker and modulator of CAR-T cell function, and may inform further CD276 CAR engineering strategies."

CAR T-Cell Therapy • IO biomarker • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CD276 • CD4 • CD8 • IFNG • IL2 • TNFA

ITGB6 modulates resistance to anti-CD276 therapy in head and neck cancer by promoting PF4+ macrophage infiltration. (PubMed, Nat Commun) - "Enoblituzumab, an immunotherapeutic agent targeting CD276, shows both safety and efficacy in activating T cells and oligodendrocyte-like cells against various cancers...Further investigations demonstrate that inhibiting ITGB6 restores sensitivity to PD1 antibodies in mice resistant to anti-PD1 treatment. In summary, our research reveals a resistance mechanism associated with immune checkpoint inhibitor therapy and identifies potential targets to overcome resistance in cancer treatment."

IO biomarker • Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD276 • CD8 • CX3CL1 • CX3CR1 • CXCL16 • CXCR6 • ITGB6

Neoadjuvant Enoblituzumab (MGA271) in Men With Localized Intermediate and High-Risk Prostate Cancer (clinicaltrials.gov) - P2 | N=33 | Active, not recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Jun 2024 ➔ Dec 2024

IO biomarker • Trial completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • CD276 • HAVCR2 • LAG3 • LAMP1 • PD-1 • TNFRSF9

A phase 2 randomized trial of neoadjuvant enoblituzumab versus standard of care in men with high-risk localized prostate cancer: The help elucidate and attack longitudinally (HEAT) prostate cancer randomized study. (ASCO 2024) - P2 | "The primary endpoint is recurrence-free survival (RFS) defined as any metastasis events, local pelvic visceral or lymph node recurrence, detectable prostate-specific antigen (PSA), or start of subsequent local or systemic therapy (including salvage or adjuvant therapy), or death for any cause, whichever occurs first. Secondary endpoints include additional clinical and immunologic correlates."

Clinical • IO biomarker • P2 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD8 • PD-L1 • PD-L2

PHASE 2 RANDOMIZED TRIAL OF NEOADJUVANT ENOBLITUZUMABVERSUS STANDARD OF CARE IN MEN WITH HIGH-RISK LOCALIZED PROSTATE CANCER: THE HELP ELUCIDATE & ATTACK LONGITUDINALLY (HEAT) TRIAL (AUA 2024) - P2 | "The primaryendpoint is recurrence-free survival (RFS) defined as any metastasisevents, pelvic lymph node recurrence, detectable prostate-specific antigen (PSA), or start of subsequent local or systemic therapy (includingsalvage or adjuvant therapy), or death for any cause, whichever occursfirst. Secondary endpoints include additional clinical and immunologiccorrelates."

Clinical • IO biomarker • P2 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • PD-L1 • PD-L2

Phase 2 Randomized Trial of Neoadjuvant Enoblituzumab versus Standard of Care in Men with High-Risk Localized Prostate Cancer: The Help Elucidate & Attack Longitudinally (HEAT) Trial (AUA 2024) - No abstract available

Clinical • P2 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Preclinical evaluation of B7‐H3 targeting nanobody‐based CAR‐T cells in glioblastoma (ESGCT 2023) - "We incorporated a B7-H3 targeting nanobody in our 2nd generation CAR vector in comparison to a classic scFvCAR incorporating the VH and VL sequence of enoblituzumab...Altogether, we report development of a promising nanoCAR-T cell product for treatment of glioblastoma. In future, these can be armored with additional factors such as cytokines or immune checkpoint blocking moieties to overcome hurdles in the tumor microenvironment."

CAR T-Cell Therapy • IO biomarker • Preclinical • Tumor mutational burden • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CD276 • IFNG • TMB

Fully Human B7-H3 CAR T Cells Exhibit Potent Preclinical Activity Against Solid Tumors (ASGCT 2024) - "For instance, all B7-H3 CAR trials underway in the U.S. utilize CARs with scFvs derived from mAbs 376.96 or MGA271, both of murine origin...Our data demonstrate that highly effective CARs against B7-H3 can be developed using scFvs obtained from human scFv phage display libraries. Additionally, fully human B7-H3 CARs like the Y111 CAR harbor the lowest potential for immunogenicity, eliminate the need for humanization, and help streamline the path to effective clinical translation."

CAR T-Cell Therapy • IO biomarker • Preclinical • CNS Tumor • Gastrointestinal Cancer • Hepatology • Neuroblastoma • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD276

Clinical Trial of TJ271 Injection Combined With Pembrolizumab in the Treatment of Advanced Solid Tumors (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: TJ Biopharma Co., Ltd. | N=160 ➔ 0 | Trial completion date: Dec 2024 ➔ Dec 2023 | Suspended ➔ Withdrawn | Trial primary completion date: Jun 2024 ➔ Dec 2023

Combination therapy • Enrollment change • Metastases • Trial completion date • Trial primary completion date • Trial withdrawal • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Urothelial Cancer • CD276 • CD73 • PD-L1

Cellular biosensors to study protein interactions relevant to immunotherapy (ITOC 2024) - "While a mirzotamab derived scF v induces a strong signal, binding of an omburtabmab-scF v is considerably weaker and no signal can be detected with an enoblituzumab derived scF v...Lastly, it is applicable for the validation of antigen binding domains for CARs. This may accelerate the development of new, functional CAR constructs and could furthermore serve as a method to characterize the role of antigen mutations for immune escape."

IO biomarker • Oncology • CD276

Neoadjuvant Enoblituzumab (MGA271) in Men With Localized Intermediate and High-Risk Prostate Cancer (clinicaltrials.gov) - P2 | N=33 | Active, not recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Sep 2023 ➔ Jun 2024

IO biomarker • Trial completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • CD276 • HAVCR2 • LAG3 • LAMP1 • PD-1 • TNFRSF9

HEAT: Trial of Neoadjuvant Enoblituzumab vs SOC in Men With High-Risk Localized Prostate Cancer (clinicaltrials.gov) - P2 | N=219 | Recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting ➔ Recruiting

Enrollment open • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD276 • LAG3 • LAMP1 • PD-1 • TNFRSF9

MT2021-27 FT538 Recurrent Ovarian, Fallopian Tube, and Primary Peritoneal Cancer (clinicaltrials.gov) - P1 | N=33 | Suspended | Sponsor: Masonic Cancer Center, University of Minnesota | Recruiting ➔ Suspended

Trial suspension • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor

B7-H3 Inhibitors in Oncology Clinical Trials: A Review. (PubMed, J Immunother Precis Oncol) - "Particularly promising treatments are enoblituzumab for prostate cancer, 131I-omburtamab for central nervous system malignancies, and HS-20093 for small-cell lung cancer but further studies are warranted. These data will be telling of the efficacy of B7-H3 inhibitors in both hematologic and solid malignancies. This study aimed to compile available results of B7-H3 inhibitors in oncology clinical trials."

Journal • Review • Brain Cancer • CNS Tumor • Genito-urinary Cancer • Hematological Disorders • Lung Cancer • Oncology • Prostate Cancer • Small Cell Lung Cancer • Solid Tumor • CD276

High B7-H3 expression with low PD-L1 expression identifies armored-cold tumors suggesting potential anti-B7-H3 therapy in triple-negative breast cancer (SABCS 2023) - "Multiple anti-B7-H3 therapies has been raised, such as DS-7300, MGA271, MGD009, and B7-H3 chimeric antigen receptor T-cell immunotherapy (CAR-T)...In the durvalumab-dependent cohort, paclitaxel-dependent cohort, anthracycline-dependent cohort, and our recruited NAT cohort, the B7-H3highPDL1low subgroup exhibited the lowest therapeutic response. Overall, this research provides a novel subtyping strategy based on the combination of B7-H3/PD-L1 expression that could potentially be applied to predict the therapeutic responses in TNBC, and suggests a potential biomarker-guided anti-B7-H3 therapy. Based on the classifier, we can select potential beneficiaries to deliver personalized medical services."

IO biomarker • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD276 • CD8 • PD-L1

Lowering the Risk of Recurrent Prostate Cancer (Johns Hopkins University School of Medicine) - "Could blocking this protein with a checkpoint-inhibiting agent and/or immune activator be a game-changer for some men with high-risk prostate cancer? This was the focus of a recent Phase II clinical trial led by...urologist Mohamad Allaf, M.D...Based on these results...Allaf and colleagues at Harvard, Northwestern, Minnesota, and Mayo Clinic have designed a larger randomized trial for men with high-risk localized prostate cancer: The Help Elucidate & Attack Longitudinally (HEAT) Prostate Cancer Trial (NCT06014255). Enrollment will begin in February 2024."

Online posting

MacroGenics Provides Update on Corporate Progress and Third Quarter 2023 Financial Results (GlobeNewswire) - "MacroGenics’ academic collaborators plan to initiate the HEAT study, an investigator-sponsored, randomized Phase 2 clinical trial. This study is expected to commence enrollment in early 2024 and will evaluate the activity of neoadjuvant enoblituzumab given prior to radical prostatectomy in men with high-risk localized prostate cancer."

Trial status • Prostate Cancer

HEAT: Trial of Neoadjuvant Enoblituzumab vs SOC in Men With High-Risk Localized Prostate Cancer (clinicaltrials.gov) - P2 | N=219 | Not yet recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

New P2 trial • Genito-urinary Cancer • Oncology • Prostate Cancer • CD8 • GZMB

MacroGenics Provides Update on Corporate Progress and Second Quarter 2023 Financial Results (GlobeNewswire) - "MacroGenics began enrolling the TAMARACK Phase 2 study of vobra duo in patients with mCRPC under an amended protocol during the second quarter....MacroGenics anticipates enrolling a majority of the study patients in 2023 and expects to provide a clinical update in 2024. MacroGenics continues to enroll a Phase 1/2 dose escalation study of vobra duo in combination with lorigerlimab in patients with various advanced solid tumors. The Company anticipates commencing the dose expansion portion of the study by year-end 2023....Based on the recently published results from a Phase 2 investigator-sponsored study of enoblituzumab in men with prostate cancer, MacroGenics and collaborators at multiple academic institutions plan to initiate an investigator-sponsored randomized, translationally intense, neo-adjuvant prostate cancer study in a high-risk population by early 2024."

New trial • P2 data • Trial status • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Improving Immune Responses in Prostate Cancer (Northwestern Medicine) - "The findings point to enoblituzumab as a safe treatment option for prostate cancer that needs further study, said Ashley Ross...'Prostate cancer is typically thought of as an immune inactive tumor; It's not very immune responsive,' said Ross..."

Media quote

"Isn't enoblituzumab already targeting this biomarker?" (@BhaiyaJiSmiless)

Biomarker

Neoadjuvant enoblituzumab in localized prostate cancer: a single-arm, phase 2 trial. (PubMed, Nat Med) - P2 | "The present study validates B7-H3 as a rational target for therapy development in PCa with larger studies planned. The ClinicalTrials.gov identifier is NCT02923180."

IO biomarker • Journal • P2 data • Genito-urinary Cancer • Immune Modulation • Oncology • Prostate Cancer • Solid Tumor

MT2021-27 FT538 Recurrent Ovarian, Fallopian Tube, and Primary Peritoneal Cancer (clinicaltrials.gov) - P1 | N=33 | Recruiting | Sponsor: Masonic Cancer Center, University of Minnesota | Not yet recruiting ➔ Recruiting

Enrollment open • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor

6B5, an anti-human B7-H3 therapeutic antibody that enhances antibody-dependent cellular cytotoxicity and inhibits tumor growth in B7-H3-humanized mice (AACR 2023) - "Epitope mapping revealed non-overlapping B7-H3 binding epitopes of 6B5 and Enoblituzumab. Taken together, these data suggest that 6B5 is a promising therapeutic anti-human B7-H3 IgG monoclonal antibody that may find clinical application in a range of cancers, including current refractory types."

Preclinical • Brain Cancer • CNS Tumor • Gastrointestinal Cancer • Glioma • Hematological Malignancies • Lung Adenocarcinoma • Lung Cancer • Lymphoma • Neuroblastoma • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Squamous Cell Carcinoma • CD276

Novel Immunotherapy Agent Safe, Shows Promise Against High-Risk Prostate Cancers (Newswise) - "A new drug, a monoclonal antibody known as enoblituzumab, is safe in men with aggressive prostate cancer and may induce clinical activity against cancer throughout the body, according to a phase 2 study led by investigators at the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy....Coauthors of the current study were Angelo M. De Marzo..."