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  • 1
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    Abstract B124: Preclinical development of a novel therapeutic antibody to treat pancreas and colorectal cancers
    American Association for Cancer Research (AACR) ; 2009
    In:  Molecular Cancer Therapeutics Vol. 8, No. 12_Supplement ( 2009-12-10), p. B124-B124
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 8, No. 12_Supplement ( 2009-12-10), p. B124-B124
    Abstract: NPC-1C is a chimeric monoclonal antibody being developed as a novel biological treatment for pancreatic and colorectal cancers. This antibody was selected from a panel of hybridomas generated from mice immunized with semi-purified membrane-associated proteins derived from biologically screened, pooled human allogeneic colon cancer tissues. NPC-1C appears to recognize an aberrantly expressed form of MUC5AC expressed specifically by human colon and pancreatic tumor tissues and cell lines. NPC-1C does not cross-react with normal human tissues (and with MUC5AC from other type of cancers), however, except for occasional, weak binding to certain GI tract tissues, which may indicate a pre-malignant state. In vitro, the NPC-1C antibody exhibits specific ADCC activity against human colon and pancreatic tumor cells, but not against control tumor cell lines. In vivo, the anti-tumor efficacy of NPC-1C was tested using preestablished subcutaneous human pancreatic tumor xenograft models. The data showed significant, and reproducible, anti-tumor action, including some complete tumor regressions. The clinical application for this antibody was bolstered by several examples of human tumor tissues were stained with biotin-conjugated NPC-1C which show a strong correlation of NPC-1C staining against pancreatic and colon tumors, with approximately 45% of tumors staining strongly positive. The staining pattern was typical of mucin expression, but also showed cytoplasmic and cell membrane staining. The pre-clinical toxicity profile of NPC-1C in normal BALB/c mice demonstrated little, if any, toxicity following single or multiple intravenous injections of 10 mg/kg, 50 mg/kg, or 100 mg/kg of clinical-grade NPC-1C antibody. Toxicity parameters measured include body weight, food consumption, complete blood analysis, serum chemistries, gross pathology, and microscopic histopathology. The bio-distribution of radio-labeled NPC-1C in mice with pre-established subcutaneous human tumors revealed specific accumulation of NPC-1C at the tumor site, with little or no binding or accumulation in several major organ systems. Finally, we studied the cytokine and antibody responses to NPC-1C in the pre-clinical mouse model. Although anti-NPC-1C antibodies were detected (as expected) in a time-dependent fashion, we did not detect changes in Type I (IL-2 or g-IFN) and Type II (IL-4 or IL-5) cytokines in response to up to 100 mg/kg of NPC-1C either 3 days or 14 days after intravenous administration. The pre-clinical development of NPC-1C indicates that it is safe and efficacious, and suggest that it should be well-tolerated and may have clinical activity in patients whose tumor expresses the altered MUC5AC epitope. The FDA has approved the Investigational New Drug (IND) application to initiate a Phase I clinical trial with NPC-1C for patients with advanced pancreatic and colorectal cancer. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B124.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-09-B124
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 2062135-8
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  • 2
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    Abstract C14: Tissue expression profile of novel tumor biomarkers identified by monoclonal antibodies.
    American Association for Cancer Research (AACR) ; 2011
    In:  Molecular Cancer Therapeutics Vol. 10, No. 11_Supplement ( 2011-11-12), p. C14-C14
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 11_Supplement ( 2011-11-12), p. C14-C14
    Abstract: Background: Monoclonal antibodies (mAbs) were raised against human colon tumor tissue extracts. Antibodies that specifically recognized tumor tissues, but did not cross-react with normal tissues, were selected for further characterization and development as diagnostic reagents and therapeutic candidates. Three mAbs that react with variant forms of MUC5AC, CEACAM molecules, and A33 were identified. The immunohistochemical staining profiles of these antibodies (NEO-101, NEO-201, and NEO-301) will be discussed. Methods: The three antibodies (NEO-101, NEO-201, and NEO-301) were each biotin-labeled, and used to stain a variety of tumor and normal human tissue types, typically at 10 ug/mL. Binding of the primary antibody was detected using streptavidin-HRP conjugate. Slides were reviewed and scored by light microscopy. Results: The NEO-101 antibody recognizes a variant form of MUC5AC expressed by colorectal (79%) and pancreatic (48%) cancer tissues. NEO-101 did not significantly cross-react with normal colon or pancreas tissues. Staining appeared to be cytoplasmic, membrane-associated, and elaborated into the lumenal spaces of positively stained tissues. The NEO-201 antibody recognizes variant forms of both CEACAM-5 and CEACAM-6. NEO-201 reacts with a wider variety of tumor tissue types including colorectal (98%), pancreatic (80%), lung (71%), stomach (100%), esophagus (61%), breast (31%), and ovarian (31%). Cross-reactivity to normal tissues was weak and sporadic. The NEO-301 antibody recognizes a variant form of A33, that is expressed by colorectal (46%), pancreatic (52%), lung (65%), and breast (45%) tumor tissues. NEO-301 also does not cross-react significantly with normal tissues. Antibodies NEO-201 and NEO-301 stained both cytoplasm and membranes of tissues examined. Conclusions: NEO-101, NEO-201, and NEO-301 antibodies react specifically with tumor tissues without significant cross-reactivity to normal tissues, an attractive characteristic for developing effective therapeutic and diagnostic products for oncology indications. We suggest that the antigens they react with are novel variants of commonly known wild type proteins that can be used as biomarker since they do not cross-react with healthy tissues. Interestingly, although these 3 antibodies were generated from extracts of pooled human colon tumor tissues, the variant antigens they cross-react with are not restricted to expression by colon tumor tissues, supporting the idea that variant protein expression may be a general property of tumor cells compared to normal cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C14.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-11-C14
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2062135-8
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  • 3
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    Prostate Specific Antigen Working Group Guidelines on Prostate Specific Antigen Doubling Time
    Ovid Technologies (Wolters Kluwer Health) ; 2008
    In:  Journal of Urology Vol. 179, No. 6 ( 2008-06), p. 2181-2186
    Details
    In: Journal of Urology, Ovid Technologies (Wolters Kluwer Health), Vol. 179, No. 6 ( 2008-06), p. 2181-2186
    Type of Medium: Online Resource
    ISSN: 0022-5347 , 1527-3792
    URL: Article
    DOI: 10.1016/j.juro.2008.01.099
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2008
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  • 4
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    Overall Survival Analysis of a Phase II Randomized Controlled Trial of a Poxviral-Based PSA-Targeted Immunotherapy in Metastatic Castration-Resistant Prostate Cancer
    American Society of Clinical Oncology (ASCO) ; 2010
    In:  Journal of Clinical Oncology Vol. 28, No. 7 ( 2010-03-01), p. 1099-1105
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 28, No. 7 ( 2010-03-01), p. 1099-1105
    Abstract: Therapeutic prostate-specific antigen (PSA) –targeted poxviral vaccines for prostate cancer have been well tolerated. PROSTVAC-VF treatment was evaluated for safety and for prolongation of progression-free survival (PFS) and overall survival (OS) in a randomized, controlled, and blinded phase II study. Patients and Methods In total, 125 patients were randomly assigned in a multicenter trial of vaccination series. Eligible patients had minimally symptomatic castration-resistant metastatic prostate cancer (mCRPC). PROSTVAC-VF comprises two recombinant viral vectors, each encoding transgenes for PSA, and three immune costimulatory molecules (B7.1, ICAM-1, and LFA-3). Vaccinia-based vector was used for priming followed by six planned fowlpox-based vector boosts. Patients were allocated (2:1) to PROSTVAC-VF plus granulocyte-macrophage colony-stimulating factor or to control empty vectors plus saline injections. Results Eighty-two patients received PROSTVAC-VF and 40 received control vectors. Patient characteristics were similar in both groups. The primary end point was PFS, which was similar in the two groups (P = .6). However, at 3 years post study, PROSTVAC-VF patients had a better OS with 25 (30%) of 82 alive versus 7 (17%) of 40 controls, longer median survival by 8.5 months (25.1 v 16.6 months for controls), an estimated hazard ratio of 0.56 (95% CI, 0.37 to 0.85), and stratified log-rank P = .0061. Conclusion PROSTVAC-VF immunotherapy was well tolerated and associated with a 44% reduction in the death rate and an 8.5-month improvement in median OS in men with mCRPC. These provocative data provide preliminary evidence of clinically meaningful benefit but need to be confirmed in a larger phase III study.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2009.25.0597
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2010
    detail.hit.zdb_id: 2005181-5
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  • 5
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    Immunotherapy for biochemically recurrent prostate cancer.
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 6_suppl ( 2018-02-20), p. 215-215
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 6_suppl ( 2018-02-20), p. 215-215
    Abstract: 215 Background: Annually about 30-50,000 men are diagnosed with biochemically recurrent prostate cancer (BCRpc), defined by a rising PSA after radical prostatectomy (RP) or definitive radiation therapy (RT) with negative conventional imaging (CT and bone scan). Standard treatments include salvage therapies, androgen deprivation or surveillance. The role of immunotherapy in BCRpc is undefined. Methods: This study evaluates PROSTVAC, a pox-viral based therapeutic cancer vaccine targeting PSA, in BCRpc. Key eligibility criteria include PSA 〉 0.8 after RP or 〉 2.0 after RT with a maximum PSA of 30, PSA doubling time (DT): 5-15 months; testosterone 〉 100, negative CT and bone scan. Patients (pts) are randomized to vaccine for 6 months or 6 months surveillance followed by 6 months of vaccine. In a post hoc analysis delayed PSA declines were characterized as a confirmed PSA decline after an intra-study apex PSA (ISAP) defined by a peak PSA affirmed by a contiguous PSA within 10% (to exclude lab variations). 80 pts will be enrolled at NCI, Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center. Results: Of the 26 pts enrolled thus far, 22 have been followed for 〉 9 months after vaccine and are evaluable. On-study median values were age 66.8 years (54-78), PSA 2.67 ng/ml (0.83-28.5), PSA DT 7.5 months (5.1-14.9). 8 pts (38%) had delayed PSA declines after ISAP (-12% to -99%). Of 13 pts on surveillance for 6 months, only one pt had a similar decline lasting only 56 days. Conclusions: Preliminary data from this study suggests that PROSTVAC may be associated with delayed, but sustained PSA declines in BCRpc which are rarely seen in surveillance alone. Additional data will be acquired from this study, but this provides rationale to develop immunotherapy combinations in BCRpc. Clinical trial information: NCT02649439. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.6_suppl.215
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
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  • 6
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    Comparison of survival of African-American (AA) patients (pts) in docetaxel (D)-based combination therapies in metastatic castrate-resistant prostate cancer (mCRPC).
    American Society of Clinical Oncology (ASCO) ; 2016
    In:  Journal of Clinical Oncology Vol. 34, No. 2_suppl ( 2016-01-10), p. 272-272
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 2_suppl ( 2016-01-10), p. 272-272
    Abstract: 272 Background: AA pts experience greater prostate cancer (PC) incidence and mortality compared to Caucasian (C) pts but are underrepresented in clinical trials (CTs). Greater representation of AAs is required to explore differences in clinical benefit in advanced disease where recent data has reaffirmed the role of D. Methods: In a retrospective analysis, baseline characteristics, Gleason score (GS), ECOG PS, number of cycles (cys), maximum prostate-specific antigen (PSA) declines, radiographic responses, overall survival (OS) and progression-free survival (PFS) were captured in 2 recent D based CTs. Results: Of 136 pts, 28 (21%) self-identified as Black or AA. Median age of AA pts is 66 (50-78 yrs). Median GS is 8 (5-10). Median ECOG PS is 1 (0-2). 15 pts have bone and soft tissue disease; 13 pts have bone only disease. Median number of cys is 28.5 (1-63). Of 27 evaluable pts, 26 had PSA declines (-26 to -99%). Radiographic responses include 11 (39%) partial responses and 16 (57%) pts with stable disease. Median OS for AAs is 29.0 months (mos) (95% CI: 20.9-34.7 mos); median PFS is 21.5 mos (95% CI: 13.7-28.9 mos). Median OS for all non-AA pts is 24.8 mos (95% CI: 21.8-29.5 mos); median PFS is 16.1 mos (95% CI: 14.1-20.1 mos). The VEGF-634G 〉 C SNP, associated with a more aggressive phenotype of PC, was evaluated in 54 pts. No evidence was found that genotype frequency varies between C and AA pts. Conclusions: In this analysis, AA pts did not have inferior OS (29 mos) or PFS (21.5 mos) outcomes compared to non-AA pts (24.8, 16.1 mos). Further analysis from larger studies is required to determine differential benefits of D for AA pts compared to non-AA pts. Clinical trial information: NCT00089609, NCT00942578.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2016.34.2_suppl.272
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2016
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  • 7
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    Phase 1 with expansion cohorts in a study of NEO-201 in adults with chemo-resistant solid tumors.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. TPS2645-TPS2645
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. TPS2645-TPS2645
    Abstract: TPS2645 Background: NEO-201 is a novel humanized IgG1 monoclonal antibody (mAb) generated against the Hollinshead allogenic colorectal cancer vaccine platform. Briefly, tumor-associated antigens (TAA) derived from tumor membrane fractions pooled from colorectal cancer surgical specimens were screened for delayed-type hypersensitivity and evaluated in clinical trials. The original vaccine was used to generate monoclonal antibodies, one of which is NEO-201. In preclinical data generated in our laboratory, we have demonstrated that NEO-201 exert anti-tumor activity by natural killer (NK)-mediated antibody-dependent cytotoxicity (ADCC) against several tumor type including colorectal and pancreatic cancer models (Fantini, et al. 2018). We have identified NEO-201 antigen as a glycosylated form of CEACAM-5 and -6, which is expressed by tumor tissue but is not present in the surrounding healthy tissue (David, et al. 2018). This could result in a specific anti-tumor activity without significant normal tissue toxicity. Nevertheless, toxicity was further assessed in non-human primates and transient neutropenia was the only adverse event observed. Based on this data we designed a first in human phase I trial to evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics (PK) and pharmacodynamics (PD) of the humanized monoclonal antibody NEO-201. Methods: This is a first-in-human phase 1 study with expansion cohort to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of NEO-201 in adults with advanced solid tumors that have high likelihood pof expression NEO201 antigen and have progressed to standard of treatments and have a PS0-2 ECOG. Study design is a classic Fibonacci (3+3) dose escalation, with a cohort expansion at the MTD. NEO-201 is administered intravenously every two weeks, and four different dose levels will be explored (DL1 = 1mg/kg, DL2 = 2mg/kg, DL3 = 4mg/kg and DL4 = 6mg/kg). No intra-patient dose escalation is allowed. Patients will be evaluated for safety every two weeks, with weekly laboratory testing, according to CTCAEv4.0. and with a DLT window of 28 days (cycle 1). Response will be assessed every 8 weeks (2 cycles of treatment) according to RECISTv1.1. Additionally, biological samples will be collected to understand NEO-201 pharmacokinetic, the effect on the immune process and their correlation with treatment toxicity and response. As of February 2019 we have completed enrollment in the first DL and are evaluating for DLT. Clinical trial information: NCT03476681.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.TPS2645
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
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  • 8
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    Phase I with expansion cohorts in a study of NEO-201 in adults with chemo-resistant solid tumors.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 4_suppl ( 2020-02-01), p. 129-129
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 4_suppl ( 2020-02-01), p. 129-129
    Abstract: 129 Background: NEO-201 is a humanized IgG1 monoclonal antibody (mAb) generated against tumor-associated antigens (TAA) from colorectal cancer. Our preclinical data demonstrated that NEO-201 exerts anti-tumor activity by NK-mediated ADCC and CDC against several tumor types. We identified NEO-201 antigen as a tumor-associated form of CEACAM-5 and -6, which is expressed by tumor tissue but is not present in the surrounding healthy tissue. Methods: This is a first-in-human phase 1 study to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of NEO-201 in adults with advanced solid tumors that have high likelihood of expression NEO201 antigen and have progressed to standard of treatments. This is a classic 3+3 dose escalation, with cohort expansion at the MTD. NEO-201 is administered intravenously every two weeks, and at four dose levels (DL1 = 1mg/kg, DL2 = 2mg/kg, DL3 = 4mg/kg and DL4 = 6mg/kg). Patients are evaluated for safety according to CTCAEv5.0., and for response according to RECISTv1.1. Biological samples are collected to understand NEO-201 pharmacokinetics, the effects on immune profile and the correlation with treatment toxicity and response. Results: Here we report the safety data and pharmacokinetics from DL1 and 2. A total of 9 evaluable patients were enrolled. Prolonged neutropenia, defined as ³G2 neutropenia lasting for 〉 7 days, was observed at DL2. The cohort was expanded to a total of 6 patients and no further DLTs were observed. Seven out of nine of the patients enrolled had colon cancer, two had pancreatic cancer and one had hormone positive breast cancer. The most frequent treatment-related AEs were infusion reaction which was observed in all patients, and moderate fatigue (33%). Best response was SD observed in two patients (one on each of DL1 and DL2). Dose escalation continues on DL3 and DL4. NEO201 antigen expression in patient tumor tissue, circulating CEACAM6/CEACAM5, and MICA will be evaluated to correlate with response and toxicity. Conclusions: NEO201 has shown some promising activity. PK and PD studies are ongoing to better understand dosing schedule, toxicity profile and to identify biomarkers for patient selection. Clinical trial information: NCT03476681.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.4_suppl.129
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 9
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    Phase II trial of bevacizumab and lenalidomide with docetaxel and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC).
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 5_suppl ( 2012-02-10), p. 207-207
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 5_suppl ( 2012-02-10), p. 207-207
    Abstract: 207 Background: Angiogenesis may be vital to mCRPC. Previously, we had shown the potent anti−tumor activity of dual antiangiogenic therapy by combining thalidomide (T) and bevacizumab (B) with docetaxel (D) and prednisone (P) in mCRPC (Ning JCO 2010). We hypothesized that combining lenalidomide (L), an analogue of T, with B, D, and P would have a more favorable efficacy/toxicity profile. Methods: All patients (pts) had chemotherapy−naïve mCRPC. 3 pts received R 15 mg daily, 3 pts had 20 mg daily, and the rest had 25 mg daily for 14 days of every 21−day cycle (C). All pts received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and enoxaparin daily throughout each C. Pegfilgrastim was given on day 2. PSA was assayed each C with imaging after C2 and then after every 3C. Results: 47 of the planned 51 pts have been enrolled. Median age was 66 (51−82), Gleason score 8 (5−10), on−study PSA 91.6 ng/ml (0.15−3520), pre−study PSA doubling time 1.43 months (0.52−6.73), number of Cs 14 (1−31), and PFS was 19.3 months as of this analysis. Among 45 pts who have completed ≥2 cycles, 39 (86.7%) and 30 (66.7%) had PSA declines of ≥50% and ≥75%, respectively. Of 29 pts with measurable disease there were 2 CR, 21 PR, and 6 SD (79.3% overall RR). 10/47 pts were taken off study for radiographic disease progression and 5/47 for other reasons. Grade ≥3 toxicities included neutropenia (24/47), anemia (9/47), thrombocytopenia (5/47), weight loss (1/47), hypertension (3/47), and febrile neutropenia (4/47). Other toxicities included perianal fistula (3/47), rectal fissure (1/47), myocardial infarction (1/47), and osteonecrosis of the jaw (ONJ) (16/47, 34.0%). At the time of diagnosis of ONJ, 9/16 pts were on bisphosphonates and 3/16 had used bisphosphonates previously. Although the incidence of ONJ was higher than the 18.3% reported by Ning, a recent study of carboplatin plus weekly docetaxel reported an incidence of 29.3%. Conclusions: Dual antiangiogenic therapy with, B and L, plus D and P was associated with high PSA (86.7%) and tumor (79.3%) responses with manageable toxicities. Further studies are underway to explore the high incidence of ONJ.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.5_suppl.207
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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  • 10
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    Correlation of clinical activity of NEO201 mAb with the expression of NK activation markers and levels of soluble factors.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. e15002-e15002
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. e15002-e15002
    Abstract: e15002 Background: NEO-201 is a humanized IgG1 mAb that targets tumor-associated variants of CEACAM-5/6. NEO201 exerts anti-tumor activity by (NK)-mediated ADCC, CDC, and by enhancing NK cell cytotoxicity through blockade of CEACAM5-CEACAM1 interaction. The first in human phase I clinical trial is ongoing. Neutropenia caused DLT and was observed at 2mg/kg (DL 2). At DL2, 2/6 patients with colorectal cancers had stable disease. In the present study we evaluated the correlation between response, NK status, and profiles of soluble factors. Methods: This is a classic 3+3 dose escalation. NEO-201 is administered intravenously every 2 weeks, with 4 dose levels planned (DL1 = 1mg/kg, DL2 = 2mg/kg, DL3 = 4mg/kg and DL4 = 6mg/kg). So far, 3 patients received DL1 and 6 patients DL2. Safety is evaluated according to CTCAEv5.0, and response according to RECISTv1.1. Biological samples are collected at baseline, at 4, 24 and 72 hours after the first dose, and before C1D15 dose to understand NEO-201 pharmacokinetics (PK), effects on immune profile and correlation with treatment toxicity and response. CD56 + /CD16 + NK cells were evaluated for modulation of NKG2D, CD107a, NKp46 (activation markers), and CEACAM1 (inhibitory marker) by flow cytometry. Soluble factors (cytokines, sMICA and sCEACAM5) were evaluated by ELISA. Results: Among the 3 patients achieving radiological SD, one (DL1) had clinical progression (PD) without radiological progression after 2 cycles due to mucous producing disease, a second patient (DL2) went off study after 2 cycles for drug unrelated issues, and the third patient (DL2) has stable disease (SD) for 6 months without significant toxicity. All other patients had radiologic PD after 2 cycles. Interestingly, baseline CD56 + /CD16 + NK cells from the two patients with SD showed an increase in NKG2D, CD107a and NKp46, and a low expression of CEACAM1. They also had low serum levels of sMICA, sCEACAM5 and IL-6. On contrary, CD56 + /CD16 + NK cells from patients with PD had low expression of NKG2D and CD107a, high expression of CEACAM1, and high levels of sMICA. Conclusions: High expression of activating markers and low expression of CEACAM1 on CD56 + /CD16 + NK cells, as well as low levels of sMICA and sCEACAM5 correlate with clinical response to NEO-201. Thus, the activity of NK cells may serve as predictors for efficacy of tumor-targeting antibody therapy. Further correlation of these biomarkers with PK and CEACAM1/5/6 expression in patients’ tissue samples will provide further support for optimizing the use of NEO201. Clinical trial information: NCT03476681 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.e15002
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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