Phase 2 trial results of DN24-02, a HER2-targeted autologous cellular immunotherapy in HER2+ urothelial cancer patients (pts).

Bajorin, Dean F.; Sharma, Padmanee; Quinn, David I.; Plimack, Elizabeth R.; Hoffman-Censits, Jean H.; O’Donnell, Peter H.; Siefker‐Radtke, Arlene O.; Sheikh, Nadeem A.; LIll, Jennifer Susan; Trager, James; Gomella, Leonard G.

doi:10.1200/jco.2016.34.15_suppl.4513

Cited by 15 publications

(9 citation statements)

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“…Genomic amplification of HER2 is common and increases the number of potentially targetable cases to over 20% . However, response to anti‐HER2 therapies have largely yielded negative results in muscle‐invasive bladder cancer . A clinical trial conducted with lapatinib, a dual tyrosine kinase inhibitor for EGFR and ERBB2, saw no improvement in progression‐free survival for 232 HER2 + patients with metastatic UC .…”

Section: Therapeutic Opportunities For Molecular Profiling In Muscle‐mentioning

confidence: 99%

“…A clinical trial conducted with lapatinib, a dual tyrosine kinase inhibitor for EGFR and ERBB2, saw no improvement in progression‐free survival for 232 HER2 + patients with metastatic UC . Other therapeutic approaches for HER2 + bladder cancer patients include a phase 2 trial of DN24‐02, a cellular immunotherapy with HER2‐derived antigen linked to granulocyte macrophage colony‐stimulating factor, but no significant differences in overall survival or distant recurrence‐free survival were observed . These poor historical response rates to HER2 inhibitors may be a function of the requirement for HER2 receptor heterodimerization with other members of the EGFR receptor family for signaling.…”

Section: Therapeutic Opportunities For Molecular Profiling In Muscle‐mentioning

confidence: 99%

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Molecular profiling in muscle‐invasive bladder cancer: more than the sum of its parts

Sjödahl

Jackson

Bartlett

et al. 2019

The Journal of Pathology

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Bladder cancers are biologically and clinically heterogeneous. Recent large-scale transcriptomic profiling studies focusing on life-threatening muscle-invasive cases have demonstrated a small number of molecularly distinct clusters that largely explain their heterogeneity. Similar to breast cancer, these clusters reflect intrinsic urothelial cell-type differentiation programs, including those with luminal and basal cell characteristics. Also like breast cancer, each cell-based subtype demonstrates a distinct profile with regard to its prognosis and its expression of therapeutic targets. Indeed, a number of studies suggest subtype-specific differential responses to cytotoxic chemotherapy and to therapies that inhibit a number of targets, including growth factors (EGFR, ERBB2, FGFR) and immune checkpoint (PD1, PDL1) inhibitors. Despite burgeoning evidence for important clinical implications, subtyping has yet to enter into routine clinical practice. Here we review the conceptual basis for intrinsic cell subtyping in muscle-invasive bladder cancer and discuss evidence behind proposed clinical uses for subtyping as a prognostic or predictive test. In deliberating barriers to clinical implementation, we review pitfalls associated with transcriptomic profiling and illustrate a simple immunohistochemistry (IHC)-based subtyping algorithm that may serve as a faster, less expensive alternative. Envisioned as a research tool that can easily be translated into routine pathology workflow, IHC-based profiling has the potential to more rapidly establish the utility (or lack thereof) of cell type profiling in clinical practice. Conflict of interest statement: DrBerman has served as a paid scientific advisor to Janssen Pharmaceuticals, which manufactures erdafitinib. cancers that invade the muscular bladder wall, commonly referred to as muscle-invasive bladder cancers. This focus reflects the scarcity of molecular subtype studies identified in more superficial bladder cancers,Non-luminal-like MIBCs are often casually referred to as 'basal-like', a simplification that clearly underestimates the variety of MIBC molecular phenotypes. About two-thirds of non-luminal-like MIBCs show strong expression of basal genes including KRT5, KRT6, KRT14, CD44, CDH3, and EGFR. This molecular subtype shows relatively high levels of both stromal-

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Section: Therapeutic Opportunities For Molecular Profiling In Muscle‐mentioning

confidence: 99%

Section: Therapeutic Opportunities For Molecular Profiling In Muscle‐mentioning

confidence: 99%

Molecular profiling in muscle‐invasive bladder cancer: more than the sum of its parts

Sjödahl

Jackson

Bartlett

et al. 2019

The Journal of Pathology

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“…In subgroup analysis, patients with low tumor burden exhibited more favorable hazard ratios for OS; however, DN24-02 failed to increase OS or recurrence-free survival in the overall group. This study was terminated early due to administrative reasons [83]. CTAs are tumor-associated antigens that elicit a robust immune response and have shown variable expressions in various malignancies.…”

Section: Vaccinesmentioning

confidence: 99%

Current Status and Future Perspectives of Immunotherapy for Locally Advanced or Metastatic Urothelial Carcinoma: A Comprehensive Review

Kim

Koo

2020

Cancers

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Advancements in the understanding of tumor immunology in urothelial carcinoma (UC) have led to U.S Food and Drug Administration (FDA) approval of five novel anti-programmed cell death protein-1/ligand 1 (PD-1/L1) checkpoint inhibitors. In 2017, the anti-PD-L1 antibody atezolizumab and the anti-PD-1 antibody pembrolizumab gained approval for use in cisplatin-ineligible patients with locally advanced and metastatic UC. These approvals were based on single-arm trials, IMvigor210 (atezolizumab) and KEYNOTE-052 (pembrolizumab). Since then, additional checkpoint inhibitors, including avelumab, durvalumab, and nivolumab, have gained approval. Preliminary results suggest additional benefits with combinations of these agents in both first- and subsequent-line therapies, inferring a paradigm shift in the future treatment approach in advanced UC. Ongoing clinical trials will investigate how to utilize predictive biomarkers for optimal patient selection and to incorporate immunotherapy into earlier lines of multimodal treatment. In this comprehensive review, we summarize the evidence supporting the use of checkpoint inhibitors for patients with UC, and highlight ongoing clinical trials that are investigating novel combinations of immunotherapy in various disease settings.

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“…However, patients with a lower disease burden and no prior neoadjuvant chemotherapy were found to have a trend towards improved survival. 9 As an alternative to recombinant peptide loading, Podrazil et al pulsed immature autologous DCs with irradiated LNCaP prostate cancer cells (DCVAC/PCa), prior to maturation with poly I:C and then subcutaneous administration to the patient. The injections were repeated up to 10 times, were preceded by 7 days of metronomic cyclophosphamide and initially co-administered with 6 cycles of docetaxel chemotherapy.…”

Section: Dendritic Cell Therapiesmentioning

confidence: 99%

Evolving adoptive cellular therapies in urological malignancies

Wong

Joshi

Pulé

et al. 2017

The Lancet Oncology

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Immunotherapies have long been used to treat urological cancers but rarely lead to cure. In the past 5 years, success of immune checkpoint inhibition has led to a resurgence of enthusiasm for immunotherapy in the treatment of solid tumours. Increased understanding of tumour immune biology, technological advancements of gene transfer and cell culture, and improved clinical infrastructures for routine delivery of cell products, has made cell-based immunotherapeutics a real prospect for cancer therapy. These scientific and clinical activities, attempting to exploit the innate and adaptive immune systems for therapeutic gain, are well exemplified by the urological malignancies of renal, bladder, prostate, and penile cancer, a group of anatomically localised diseases, each with a distinct biology and different immunotherapeutic challenges. In this Review, we present the results of clinical studies investigating autologous cellular therapies in urological malignancies. Specifically, we discuss the rationale for upcoming studies, and how novel therapies and adoptive cell combinations can be used for personalised cancer therapy.

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Phase 2 trial results of DN24-02, a HER2-targeted autologous cellular immunotherapy in HER2+ urothelial cancer patients (pts).

Cited by 15 publications

References 0 publications

Molecular profiling in muscle‐invasive bladder cancer: more than the sum of its parts

Molecular profiling in muscle‐invasive bladder cancer: more than the sum of its parts

Current Status and Future Perspectives of Immunotherapy for Locally Advanced or Metastatic Urothelial Carcinoma: A Comprehensive Review

Evolving adoptive cellular therapies in urological malignancies

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