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Modest success has been achieved with the use of high-dose cytotoxic therapy and bone marrow transplantation in solid tumors. Patient outcome can potentially be improved with further intensification of the therapy. The rapid hematologic recovery achieved with mobilized peripheral blood progenitor cells (PBPC) may reduce the toxicity of transplantation enabling the use of sequential courses of myeloablative therapy. We report on 42 patients with solid tumors enrolled in a tandem transplant protocol involving the use of PBPC mobilized with cyclophosphamide (4 g/m2), etoposide (1 g/m2), and granulocyte-colony-stimulating factor (G-CSF: 10 micrograms/kg/day). This regimen significantly increased the number of circulating progenitor cells; only 1-2 aphereses were sufficient to collect 2.5 x 10(8)/kg mononuclear cells, our goal for each transplant course. The median number of circulating colony-forming units (CFU) and CD34+ cells obtained for each transplant course were 70.3 x 10(4)/kg, and 11.7 x 10(6)/kg, respectively. There was a significant correlation between the numbers of CD34+ cells and CFU measured in the apheresis product (r = 0.49, P = .003). The first transplant regimen given to 38 patients consisted of thiotepa, carboplatin, and cyclophosphamide. The second transplant regimen given to 29 patients consisted of busulfan and etoposide. Hematologic recovery was comparable after each of the two transplant courses. The median time to neutrophil recovery over 0.5 x 10(9)/L and to platelet transfusion independence was 9 and 8 days, respectively. There was no difference in engraftment rates after transplant with PBPC only (n = 28 courses) compared to transplant with PBPC plus bone marrow (n = 39 courses).(ABSTRACT TRUNCATED AT 250 WORDS)

Human peripheral blood T-cells were divided into subsets on the basis of their ability to bind to the Fc receptor portion of IgG (TG cells) or IgM (TM cells). These subsets were studied in 25 patients with newly diagnosed disseminated malignant solid tumors. When compared to a group of healthy, age-matched controls, cancer patients as a group exhibited signifcantly increased percentages of TG cells and significantly decreased percentages and numbers of TM cells. Comparison of the values determined for individual patients to those determined for groups of 10 healthy individuals in the same decade of life revealed that most cancer patients had normal levels of lymphocytes and T-cells, but many had aberrant values for T-cell subsets.

Background ZW25, a novel IgG1 bispecific antibody, targets HER2 domains ECD2 and ECD4, resulting in multiple differentiated and unique mechanisms of action, including improved receptor internalization and downregulation relative to trastuzumab. Safety, anti-tumor activity, and biomarker data from an ongoing phase 1 trial of ZW25 monotherapy in solid tumors other than breast cancer, are presented here. Methods Eligible patients with HER2 IHC 3+, IHC 2+/FISH+, or IHC 2+/FISH- tumors confirmed by central review of fresh or archival biopsies, who had progressed on all standard therapies, were enrolled. Patients were treated with single agent ZW25 at 10 mg/kg QW or 20 mg/kg Q2W Assessments included tumor evaluations (RECIST 1.1 Q8W), circulating tumor DNA (ctDNA), and standard safety evaluations. Results A total of 43 patients were treated, including 17 patients with gastroesophageal adenocarcinoma (GEA), 6 with biliary cancers, 10 with colorectal cancer, and 10 other cancers. The median number of prior therapies was 3 (range 1-6) for all patients. For GEA and non-GEA patients, 88% and 35% respectively received at least one prior HER2 therapy. The most common treatment-related adverse events (all Grade 1 or 2) were diarrhea (49%) and infusion related reaction (34%). The objective response rate (all partial response (PR)) for response evaluable patients was 41% (14/34), stable disease (SD) in 38% (13/34), and progressive disease in 21% (7/34). The majority of patients (74%; 25/34) experienced a decrease in the sum of diameters for their target lesions. Compared to FISH, the positive predictive value of HER2 amplification in pre-dose C1D1 ctDNA was 90% (95% CI 79-96%), negative predictive value 45% (25-67%), and diagnostic accuracy 79% (63-90%). Disease control (PR or SD) > 5 months was associated with lower level of copy number adjusted mutational variant allele frequency in pre-treatment ctDNA (Mann Whitney p = 0.0085). Conclusions ZW25 has been well tolerated with promising single agent activity in heavily pre-treated patients. These data support further clinical development of this bispecific antibody in HER2-expressing solid tumors. Clinical trial identification Identifier: NCT02892123. Legal entity responsible for the study Zymeworks Inc. Funding Zymeworks Inc. Disclosure D-Y. Oh: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Novartis; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Bayer; Advisory / Consultancy: Taiho; Advisory / Consultancy: ASLAN; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Zymeworks; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Novartis; Research grant / Funding (self): Array; Research grant / Funding (self): Eli Lilly; Research grant / Funding (self): Green Cross. E. Hamilton: Speaker Bureau / Expert testimony: Genentech/Roche; Advisory / Consultancy: Flatiron Health; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Casadian Therapeutics; Research grant / Funding (self): Zymewors; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Casadian Therapeutics; Research grant / Funding (self): Hutchinson. M. Beeram: Speaker Bureau / Expert testimony: Genentech. K-W. Lee: Honoraria (self): BMS; Honoraria (self): Eli Lilly; Research grant / Funding (self): ALX Oncology; Research grant / Funding (self): Array BioPharma; Research grant / Funding (self): ASLAN Pharma; Research grant / Funding (self): AstraZeneca/MedImmune; Research grant / Funding (self): Five Prime; Research grant / Funding (self): Green Cross Corp; Research grant / Funding (self): LSK BioPharma; Research grant / Funding (institution): Macrogenics; Research grant / Funding (self): Merck MGaA; Research grant / Funding (self): MSD; Research grant / Funding (self): Ono Pharma; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Pharmacyclics; Travel / Accommodation / Expenses: BMS. Y-K. Kang: Advisory / Consultancy: ONO; Advisory / Consultancy: BMS; Advisory / Consultancy: Daehwa; Advisory / Consultancy: LSK BioPharma; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Macrogenics; Advisory / Consultancy: Zymeworks; Advisory / Consultancy: Blue print; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Novartis; Advisory / Consultancy: Astellas; Research grant / Funding (self): Roche; Research grant / Funding (self): Novartis. J. Chaves: Honoraria (self): PLLC. C. Vaklavas: Advisory / Consultancy: Genentech; Advisory / Consultancy: Daiichi-Sankyo; Research grant / Funding (self): Genentech; Research grant / Funding (self): Roche; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Incyte; Research grant / Funding (self): Novartis; Research grant / Funding (self): Pharmacyclics; Research grant / Funding (self): Tracon; Research grant / Funding (self): Innocrin; Research grant / Funding (self): Zymeworks; Research grant / Funding (self): H3 Biomedicine. E. Elimova: Advisory / Consultancy: BMS; Honoraria (self): Zymeworks; Spouse / Financial dependant, Spouse: Merck employee in vaccine global division: Merck. C. Ferrario: Honoraria (self): Pfizer; Honoraria (self): Bayer; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): Merck; Honoraria (self): Astellas; Advisory / Consultancy: Genomic health; Advisory / Consultancy: Merck; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Speaker Bureau / Expert testimony: Novartis; Research grant / Funding (self): Amgen; Research grant / Funding (self): Astellas; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Bayer; Research grant / Funding (self): Casadian Therapeutics; Research grant / Funding (self): Celldex; Research grant / Funding (self): Lilly; Research grant / Funding (self): Merck; Research grant / Funding (self): Novartis. A. Fortenberry: Shareholder / Stockholder / Stock options, Full / Part-time employment: Zymeworks. G. Rowse: Shareholder / Stockholder / Stock options, Full / Part-time employment: Zymeworks. T. Gray: Shareholder / Stockholder / Stock options, Full / Part-time employment: Zymeworks. R. Lai: Shareholder / Stockholder / Stock options, Full / Part-time employment: Zymeworks. F. Meric Bernstam: Research grant / Funding (self): Novartis; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Calithera; Research grant / Funding (self): Aileron; Research grant / Funding (self): Bayer; Research grant / Funding (self): Jounce; Research grant / Funding (self): CytoMx; Research grant / Funding (self): eFFECTOR; Research grant / Funding (self): Zymeworks; Research grant / Funding (self): PUMA Biotech; Research grant / Funding (self): Curis; Research grant / Funding (self): Millennium; Research grant / Funding (self): Daiichi Sankyo; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Guardant Health; Research grant / Funding (self): Takeda, Seattle Genetics, GlaxoSmithKline; Research grant / Funding (self), Travel / Accommodation / Expenses: Taiho, Genentech, Debiopharm Group, Pfizer; Consulting: Pieris, Dialectica, Sumitomo Dainippon, Samsung Bioepis, Aduro, OrigiMed, Xencor, Jackson Laboratory, Zymeworks, Kolon Life Science, Parexel Internationa; Advisory / Consultancy: Inflection Biosciences, GRAIL, Darwin Health, Spectrum, Mersana, and Seattle Genetics. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]