bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combination immunotherapy with GM-CSF and CTLA-4 blockade for hormone refractory prostate cancer: Balancing the expansion of activated effector and regulatory T cells
Authors: Fong L. , Kavanagh B. , Hou Y. , O’Brien S. , Valiente J. , Weinberg V. , Rini B. I. , Small E. J. 
Published: March 2020

3001 Background: CTLA-4 is a costimulatory molecule expressed on activated T cells that delivers an inhibitory signal to these T cells. CTLA4 blockade with antibody treatment has been shown to augment T cell responses and anti-tumor immunity in animal models. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a bone marrow growth factor for antigen presenting cells, which has also been shown to enhance anti-tumor immune responses. Methods: A phase I trial in patients with metastatic, hormone refractory prostate cancer (HRPC) was undertaken to combine these immunotherapies. Sequential cohorts of 3–6 patients were treated with escalating doses (0.5, 1.5 or 3 mg/kg) of ipilimumab, a fully human anti-CTLA-4 antibody, given IV on day 1 of each 28-day cycle × 4 cycles. Patients also received GM-CSF 250 mg/m2/d SC on days 1–14 of the 28-day cycles. Patients were monitored for toxicity as well as for T cell activation. PSA and radiographic tests were performed at baseline and through therapy to evaluate for clinical response. Results: 24 patients have been treated. Of 6 patients treated on the highest dose level (3 mg/kg ×4), 3 (50%) had confirmed PSA declines of >50%, and one of these patients had a partial response in hepatic metastases. Immune-related adverse events associated with ipilimumab treatment consisted of a grade 3 rash in 1 patient at 1.5 mg/kg, a grade 3 rash and panhypopituitarism in 1 patient at 3.0 mg/kg, and a grade 3 colitis in one patient at 3.0 mg/kg. All events were successfully managed. A dose-response relationship was seen between ipilimumab dose and effector T cell activation. Expansion of circulating CD4+ FoxP3+ regulatory T cells was also seen with treatment. Conclusions: CTLA-4 blockade combined with GM-CSF treatment induces clinical responses in HRPC. Treatment induces both the expansion of activated effector and regulatory T cells in vivo in cancer patients. Finally, CD4 and CD8 T cell activation, adverse events, and clinical responses appear to be dose-dependant. Supported by NIH SPORE P50 CA89520. No significant financial relationships to disclose.
Phase II trial of vaccination with WT1 peptide, GM-CSF, and KLH in patients with acute myeloid leukemia and myelodysplasia: Final immunological, molecular, and clinical results
Authors: Letsch A. , Scheibenbogen C. , Busse A. , Asemissen A. M. , Schmittel A. , Hofmann W. K. , Uharek L. , Blau I. W. , Thiel E. , Keilholz U. 
Published: March 2020

3008 Purpose: A phase II trial of vaccination with the HLA-A2-restricted WT1.126–134 peptide was performed in patients (pts) with AML and MDS and overexpression of WT1 to determine toxicity, immunogenicity, and molecular and clinical activity. Methods: Patients received intra/subcut. vaccinations of 0.2 mg WT1.126–134 peptide (day 3), 62.5 mcg GM-CSF (days 1–4) as DC-stimulant and 1 mg keyhole limpet hemocyanin (day 3) as T helper protein. Vaccination was biweekly x 4 followed by 4-weekly in the first 13 patients and continuously biweekly in the subsequent 13. Early disease progression until vaccine # 6 was allowed, if not requiring chemotherapy. WT1-specific T cell responses were measured by tetramer and cytokine flow cytometry. WT1 levels were assessed by qRT-PCR. Clinical response assessment followed IWG-MDS criteria, capturing stable disease and hematologic improvement. Statistical analysis was performed by frequency tables and exploratory comparisons using Fishers test. Results: Of 29 pts enrolled 25 were evaluable, 23 with AML and 2 with RAEB. 15 AML pts had >5% marrow blasts and 8 had high-risk CR with detectable WT1 mRNA. A median of 11 (range 3 - 25) vaccinations was administered, 3 pts are ongoing. No relevant toxicity occurred. There were no obvious differences in outcome parameters between the 2 vaccination schedules. The percentage of patients with WT1 tetramer response increased from 28% prior to vaccination to 80% at week 10 (p=0.003), while the WT1 peptide specific cytokine response increased from 20% to 57% (p=0.012) of patients. WT1 mRNA-levels increased in 22% of patients, were stable in 26%, and decreased in 52% (2 to>50-fold). One CR (514 days) and 13 SD (99 to 339 days) were observed, 5 SD with >50% blast reduction and 3 with hematologic improvement. The CR and 3 SD occurred after initial PD. The median time to treatment failure (TTF) was 143 days. There was a significant association between decrease in WT1 mRNA levels and TTF (p=0.026). Conclusions: This study proves immunological, molecular and clinical efficacy of WT1 peptide vaccination in AML. Further investigations are indicated in WT1 expressing carcinomas and in combination with agents targeting CTLA4 or PD1. No significant financial relationships to disclose.
Booster vaccination of non-small cell lung cancer (NSCLC) patients with MAGEA3 protein and AS02B adjuvant
Authors: Atanackovic D. , Altorki N. K. , Cao Y. , Ritter E. , Ferrara C. , Ritter G. , Hoffman E. W. , Bokemeyer C. , Old L. J. , Gnjatic S. 
Published: March 2020

3015 Background: We have previously reported results of a phase II trial of recombinant ProtD/MAGE-3/His (MAGEA3) protein 300μg administered IM every three weeks for 4 doses with or without adjuvant AS02B to NSCLC patients following resection of MAGEA3 positive disease (JI, 172:3289, 2004). We found that the presence of adjuvant was essential for the development of strong humoral and cellular responses against selected MAGEA3 epitopes. Methods: 14 of the original 18 patients received booster vaccinations. Patients who still had no evidence of disease for up to two years after receiving their original MAGEA3 protein regimen (7 in cohort 1 without adjuvant, 7 in cohort 2 with adjuvant), received 4 additional doses of MAGEA3 protein with adjuvant. T cell immunomonitoring was extended to encompass any MAGEA3 epitope using full length antigen, and the scope of analysis of humoral responses was widened. Results: After just one boost injection, 6 of the 7 patients originally vaccinated with MAGEA3 protein plus adjuvant reached the peak of antibody titers to MAGEA3 attained during the first vaccination and went on to develop a stronger response than during the first cycle. In addition, the spectrum of CD4+ and CD8+ T cells against various new and known epitopes widened with booster vaccination. In contrast, only 3/7 patients originally vaccinated with MAGEA3 protein alone seroconverted to low-titered MAGEA3 responses and showed very limited CD4+ and no CD8+ T cell reactivity, despite now receiving antigen in the presence of adjuvant. Conclusions: These results underscore the importance of proper antigen priming using an adjuvant for generating persistent B and T cell memory, allowing for typical booster responses with re-immunization. In contrast, absence of adjuvant at priming may compromise further immunization attempts. These data provide immunological rationale for vaccine design in light of recently reported favorable clinical findings in NSCLC patients following vaccination with MAGEA3 protein plus adjuvant AS02B (GSK, ASCO 2005). No significant financial relationships to disclose.
Correlation of T-cell response, clinical activity and regulatory T-cell levels in renal cell carcinoma patients treated with IMA901, a novel multi-peptide vaccine
Authors: Singh-Jasuja H. , Walter S. , Weinschenk T. , Mayer A. , Dietrich P. Y. , Staehler M. , Stenzl A. , Stevanovic S. , Rammensee H. , Frisch J. 
Published: March 2020

3017 Background: Cancer vaccines have been able to induce T-cell responses in cancer patients but rarely demonstrated a correlation of immune responses with clinical benefit. Here, we present immunological results of a phase 1 study with IMA901, a therapeutic cancer vaccine based on multiple novel synthetic tumor-associated peptides (TUMAP) identified as being naturally presented in primary renal cell carcinoma (RCC) tissues. Methods: The HLA peptidome of 32 primary RCC samples was systematically investigated using a combination of mass spectrometry, gene expression profiling and in vitro human T-cell assays. 9 HLA-A*02- and 1 HLA-DR- restricted TUMAPs derived from 9 different tumor antigens were selected and designated IMA901. 28 HLA-A*02-positive stage III/IV RCC patients were enrolled in a single arm, multicenter study and received 8 vaccinations on days 1, 2, 3, 8, 15, 22, 36, and 64 each consisting of 4.5 mg IMA901 (including a HBV-derived viral marker peptide) and 75 μg GM-CSF as immune adjuvant. T-cell responses using IFN-γ ELISPOT and HLA multimer analysis and CD4+ Foxp3+ regulatory T cell (Treg) levels were measured in peripheral blood. Results: In vivo IMA901- induced specific T-cell responses were detected to the HBV marker peptide (52% of 27 evaluable patients), at least one TUMAP (74%) or multiple TUMAPs (30%). T-cell responses were detectable already at day 15, peaked subsequently and were sustainable until follow-up in the majority of patients. Most importantly, patients eliciting multiple responses to TUMAPs significantly showed a higher clinical benefit rate (SD+PR; p=0.018) and lower Treg levels at study onset (p=0.016). No correlation of HBV marker peptide responses with either clinical benefit or Treg levels was observed. Conclusions: IMA901 rapidly induced T-cell responses in a majority of advanced RCC patients. A clinical mode of action is strongly supported by the significant correlation of multiple T-cell responses with clinical benefit. CD4+ Foxp3+ Tregs seem to play an active role in limiting the broadness of T-cell responses. Furthermore, our data suggest that we can predict in vivo immunogenicity of cancer vaccine antigens by our in vitro drug discovery approach. No significant financial relationships to disclose.
Covalent coupling of a novel TLR7 agonist to antigen elicits an effective immune response in a murine melanoma tumor model
Authors: Daniels G. A. , Chan M. , Wu C. C. , Tawatao R. , Messmer D. , Eftimie B. , Cottam H. , Carson D. 
Published: March 2020

3019 Background: Toll-like receptor (TLR) signaling triggers innate immune stimulation capable of generating an adaptive immune response under appropriate conditions. TLR agonists have shown efficacy in preclinical and clinical cancer therapies. However, one limitation to this approach has been the use of TLR agonists delivered at distances away from the target (ie-subcutaneous injections for general immune stimulation) or the inability to effectively couple antigen with adjuvant. Methods: We have synthesized a novel TLR7 agonist capable of covalent coupling to primary amines under physiologic conditions. In vitro activity of adjuvant alone or antigen-adjuvant complexes were tested for innate immune activation by utilizing bone marrow-derived murine or peripheral blood mononuclear cell-derived dendritic cells (DC) with respect to DC maturation and cytokine secretion (IL12, IL6, TGFbeta and IFNgamma). Immunocompetent syngeneic C57/b6 mice were prophylactically vaccinated with intradermal with either antigen, antigen mixed with adjuvant or antigen- adjuvant coupled complexes and challenged with B16 melanoma tumor cells expressing the cOVA transgene. Results: The effective concentration (EC50) for each compound generally followed a bell shaped distribution with higher doses being inhibitory. Maximal stimulation occurred between 10 and 1000nM. Coupled adjuvant molecules retained activity with generally lower EC50 values. Coupling 1V199 to chicken ovalbumin nearly doubled median survival from 22 to 35 days following subcutaneous tumor challenge compared with chicken ovalbumin alone. Conclusions: Covalent linkage of a TLR7 agonist to antigen stimulates DC cytokine production and protects mice from tumor challenge. Use of a soluble TLR7 agonist which retains its immune stimulating properties following coupling to antigen under physiologic conditions may be useful in the development of an in situ vaccine in solid tumor therapy. No significant financial relationships to disclose.
A pilot study of bevacizumab (Bev) and continous low-dose granulocyte-macrophage colony-stimulating factor (GM-CSF) in heavily pretreated patients with refractory solid tumors: Preliminary results
Authors: Schmidt M. , Reinhold U. , Kurbacher J. A. , Rieckmann O. , Huncke H. , Radmacher A. , Cree I. A. , Kurbacher C. M. 
Published: March 2020

3031 Bev is an important inhibitor of VEGF, a mediator of tumor-induced angiogenesis. Inhibiting generation of dendritic cells (DC) from blood and tissue precursors, VEGF is also a crucial immunosuppressive agent in anti-tumoral immunotolerance. Beyond anti-angiogenesis, inhibition of VEGF may results in an improved antineoplastic immune response, which may be further improved by GM-CSF known to effectively stimulate DCs. GM-CSF has formerly be shown to induce objective responses in refractory gynecologic and breast carcinomas [Kurbacher et al. Oncology 2005]. This ongoing prospective clinical trial was initiated to investigate the combination of Bev and GM-CSF in patients (pts) with heavily pretreated solid tumors. Toxicity was documented according to the NCI-CTC scale, responses were recorded according to the RECIST or the Rustin criteria. Statistical pre-study considerations forced termination of the trial if no responses were observed among the first 12 pts recruited. Until now, 10 pts are included: epithelial ovarian carcinoma, n=4; metastatic breast cancer, n=3; peritoneal papillary-serous carcinoma, n=2; salivary gland adenocarcinoma, n=1. Regarding their history, all pts have been considered chemo-resistant or non-treatable due to their underlying bone marrow and/organ functions. Bev was applied at a fixed dose of 6 mg/kg q2w. GM-CSF was administered sc at 125 μg/d. GM-CSF was increased every 4 weeks at 25 μg/d increments until a maximum dose of 250 μg/d until occurence of objective tumor response or leukocytosis <20,000 cells/μL. Among the 10 pts treated so far, 2 partial responses (PR), 5 stable diseases (SD), and 3 progressive diseases (PD) have been recorded accounting for an objective response rate of 20%. Median time to progression is 16 weeks, with 7 pts still alive. Toxicity was generally mild and never therapy-limiting: NCI-CTC grade (G) 2 fatigue in 3 pts, G2 flu-like symptoms and G2 in either 1 pt, G1 injection site reactions in 3 pts. Preliminary results of this trial have shown Bev plus GM-CSF to produce a promising clinical activity in heavily pretreated pts with solid tumors. Thus, pts accrual is still continuing. No significant financial relationships to disclose.
Generation of antibodies that target and kill MUC1 expressing cancer cells via a novel cell-tethered MUC1 α/β junction epitope
Authors: Karmely M. , Rubinstein D. B. , Wreschner D. H. 
Published: March 2020

3034 Background: MUC1 protein has generated considerable interest as a target for tumor killing. However, a serious shortcoming of anti-MUC1 antibodies generated to date is that they recognize epitopes within the strongly immunogenic tandem-repeat-array of the MUC1 a- chain which is released from the cell into the circulation. Soluble shed MUC1 a-chain sequesters anti-tandem-repeat-array antibodies, severely limiting their ability to reach MUC1-expressing malignant cells. Rather than target freely circulating MUC1 a-chain, we identified the junction of the MUC1 a-subunit to cell-membrane-bound MUC1 β-subunit as a preferable cell-tethered MUC1 epitope; since the site is not shed, antibodies recognizing it are more effective in targeting MUC1 expressing cells. Methods: To circumvent the immunogenicity of the a-chain tandem repeat array we formulated a novel antibody generating protocol utilizing immunization with both MUC1 cDNA and with the alternatively-spliced MUC1/X protein isoform from which the tandem repeat array is deleted. After immunization and hybridoma formation, anti- MUC1 a/β junction antibodies were selected. Results: DMC209 monoclonal antibodies uniquely specific for the MUC1 a/β junction were generated. The antibodies specifically bind the MUC1 a/β junction on full-length MUC1 expressed by breast and ovarian cancer cells, and on MUC1-positive malignant plasma cells of multiple myeloma. To demonstrate that anti-MUC1 a/β junction antibodies kill malignant cells, immunotoxin conjugates were formed with anti-MUC1 a/β junction polyclonal antibodies generated in our cDNA/protein immunization protocol and PE38, a powerful pseudomonas exotoxin. The antibody-exotoxin conjugates were potently cytocidal to MUC1-expressing malignant cells. Significantly, cell killing was abrogated by addition of soluble MUC1/X protein, highlighting that the cell-killing immunotoxin gains cell entry via the MUC1 a/β junction. Conclusions: The MUC1 a/β junction has been identified as an important cell-tethered MUC1 epitope against which highly specific antibodies can be generated capable of killing MUC1-expressing cells. These studies point to effective anti-MUC1-based immuno-therapeutic strategies. No significant financial relationships to disclose.
Natural history of diarrhea associated with the anti-CTLA4 monoclonal antibody CP-675,206
Authors: Antonia S. , Sosman J. , Kirkwood J. M. , Redman B. , Gajewski T. F. , Pavlov D. , Bulanhagui C. , Camacho L. H. , Ribas A. 
Published: March 2020

3038 Background: Diarrhea resulting from immune activation has been associated with CTLA4 blockade. For example, in patients (pts) with stage IV melanoma receiving ipilimumab (MDX-010), a number of pts developed grade 3/4 autoimmune enterocolitis and severe diarrhea (Attia et al, 2005). In a single-dose phase I trial of CP-675,206 at doses up to 15 mg/kg in pts with solid tumors (n = 39), 9 instances of diarrhea were reported including 3 grade 3 events (Ribas et al, 2005). The incidence and severity of diarrhea was assessed in pts receiving CP- 675,206 in a large phase I/II study. Methods: An open-label phase I/II trial of CP-675,206 was conducted in pts with stage III (unresectable) or stage IV melanoma and an ECOG PS = 1. Diarrhea was assessed in pts treated at the phase II doses: 10 mg/kg monthly (Q1M) in phase I (n = 22), or 10 mg/kg Q1M (n = 44) or 15 mg/kg every 3 months (Q3M, n = 45) in phase II. Results: Medians of 3.5 doses (range, 1 to 18) at 10 mg/kg Q1M in phase I, 3 doses (range, 1 to 26) at 10 mg/kg Q1M in phase II, and 1 dose (range, 1 to 9) at 15 mg/kg Q3M were administered with 100% dose compliance. Treatment-related diarrhea was reported by 43 (39%) of 111 pts, and grade 3 diarrhea occurred in 14 (13%) pts. One patient had grade 4 colitis resulting in a colectomy. Diarrhea (all grades) occurred with similar frequency in each dose group; however, grade 3 treatment-related diarrhea occurred in 8% of pts treated with 15 mg/kg Q3M compared with 18% of pts treated with 10 mg/kg Q1M in phase I and 14% of pts treated with 10 mg/kg Q1M in phase II. Among 9 pts with an objective response, 8 experienced diarrhea (3 of which were grade 3). The majority of cases (65%) were mild to moderate in severity with a median time to onset of 51 days (range, 1 to 583 days) and resolution of 8 days (range, 1 to 182 days). More than half of pts who reported serious events of diarrhea were treated with steroids. Conclusions: Diarrhea associated with CP-675,206 was primarily mild to moderate in severity, transient, and manageable. In addition, 15 mg/kg Q3M may be better tolerated than 10 mg/kg Q1M. Ongoing clinical trials in pts with advanced melanoma will provide further information about the incidence, severity, and optimal management of diarrhea associated with CP-675,206. No significant financial relationships to disclose.
Combining galiximab with the chemotherapeutic agents fludarabine or doxorubicin improves efficacy in animal models of lymphoma
Authors: Hariharan H. K. , Murphy T. , Clanton D. , Berquist L. , Chu P. , Yun T. , Molina A. , Ho S. 
Published: March 2020

3040 Background: Galiximab, a primatized monoclonal antibody that binds with high affinity to CD80 and mediates antibody- dependent, cell-mediated cytotoxicity in vitro, is currently under investigation for the treatment of follicular non-Hodgkin’s lymphoma (NHL). In a phase I/II monotherapy study, galiximab produced an overall response rate of 11%, and tumor reductions were observed in 46% of patients. Initial clinical trials also demonstrate that galiximab is well tolerated and suggest that combining galiximab with rituximab (anti-CD20) provides clinical benefit. These results are consistent with preclinical studies in murine lymphoma xenograft model systems, which demonstrate the superiority of combination therapy. Methods: To further define the therapeutic potential of galiximab, the Raji subcutaneous and the SKW disseminated lymphoma murine xenograft models were used to define the in vivo efficacy of galiximab alone or in combination with fludarabine or doxorubicin. Similar studies were performed with rituximab. Results: In the Raji model, both galiximab and rituximab exhibited maximal inhibition of the growth of preestablished (150-mg) tumors at a dose of 3 mg/kg/wk. Interestingly, higher doses of galiximab (but not rituximab) showed reduced inhibition. Galiximab (3 mg/kg/wk) inhibited tumor growth alone (P<0.0001 vs. control) and showed significantly enhanced activity when combined with fludarabine (50 or 100 mg/kg daily for 5 days; P<0.0002 vs. galiximab alone and P<0.003 vs. fludarabine alone). Similar results were observed with rituximab. In the SKW model, treatment with galiximab (5 mg/kg/wk for 6 doses) significantly enhanced survival compared with a control (P<0.0001) or doxorubicin (2.5 mg/kg/day for 3 doses; P<0.0001). Studies combining fludarabine or doxorubicin with both galiximab and rituximab are ongoing. Conclusions: Studies in animal models of lymphoma indicate that galiximab may provide clinical benefit when used in combination with chemotherapeutic agents such as fludarabine and doxorubicin, and provide a rationale for the investigation of these novel chemoimmunotherapy combinations in clinical trials. No significant financial relationships to disclose.