dendritic cell vaccine
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Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 135
Author(s):  
Roberta Coletti ◽  
Andrea Pugliese ◽  
Andrea Lunardi ◽  
Orazio Caffo ◽  
Luca Marchetti

Prostate cancer (PCa) is one of the most frequent cancer in male population. Androgen deprivation therapy is the first-line strategy for the metastatic stage of the disease, but, inevitably, PCa develops resistance to castration (CRPC), becoming incurable. In recent years, clinical trials are testing the efficacy of anti-CTLA4 on CRPC. However, this tumor seems to be resistant to immunotherapies that are very effective in other types of cancers, and, so far, only the dendritic cell vaccine sipuleucel-T has been approved. In this work, we employ a mathematical model of CRPC to determine the optimal administration protocol of ipilimumab, a particular anti-CTLA4, as single treatment or in combination with the sipuleucel-T, by considering both the effect on tumor population and the drug toxicity. To this end, we first introduce a dose-depending function of toxicity, estimated from experimental data, then we define two different optimization problems. We show the results obtained by imposing different constraints, and how these change by varying drug efficacy. Our results suggest administration of high-doses for a brief period, which is predicted to be more efficient than solutions with prolonged low-doses. The model also highlights a synergy between ipilimumab and sipuleucel-T, which leads to a better tumor control with lower doses of ipilimumab. Finally, tumor eradication is also conceivable, but it depends on patient-specific parameters.


Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5801
Author(s):  
Alexandre Harari ◽  
Apostolos Sarivalasis ◽  
Kaat de Jonge ◽  
Anne-Christine Thierry ◽  
Florian Huber ◽  
...  

Endometrial cancer (EC) is a common gynecological malignancy and the fourth most common malignancy in European and North American women. Amongst EC, the advanced serous, p53-mutated, and pMMR subtypes have the highest risk of relapse despite optimal standard of care therapy. At present, there is no standard of care maintenance treatment to prevent relapse among these high-risk patients. Vaccines are a form of immunotherapy that can potentially increase the immunogenicity of pMMR, serous, and p53-mutated tumors to render them responsive to check point inhibitor-based immunotherapy. We demonstrate, for the first time, the feasibility of generating a personalized dendritic cell vaccine pulsed with peptide neoantigens in a patient with pMMR, p53-mutated, and serous endometrial adenocarcinoma (SEC). The personalized vaccine was administered in combination with systemic chemotherapy to treat an inoperable metastatic recurrence. This treatment association demonstrated the safety and immunogenicity of the personalized dendritic cell vaccine. Interestingly, a complete oncological response was obtained with respect to both radiological assessment and the tumor marker CA-125.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1274-1274
Author(s):  
Arjan A. Van de Loosdrecht ◽  
Jacqueline Cloos ◽  
Eva Maria Wagner ◽  
Uwe Platzbecker ◽  
Tobias A. W. Holderried ◽  
...  

Abstract Background. Persistence of measurable residual disease (MRD) is a poor prognostic factor and predicts relapse in acute myeloid leukemia (AML). In a phase I study, the allogeneic leukemia-derived dendritic cell vaccine, DCP-001, has shown safety and humoral and cellular immune responses (A.A. van de Loosdrecht, et al. Cancer Immunol. Immunother. 2018;67:1505). In the current phase II study, (Clintrials.gov: NCT03697707) we report on progress and evaluation of MRD conversion, as primary endpoint, relapse free and overall survival. Methods. AML-patients, ineligible at screening for HSCT, who are in first complete remission (CR1) but with MRD receive 4 biweekly doses of 25e6 or 50e6 cells per vaccination (cells/vc) followed by 2 doses of 10e6 cells/vc as boosts at week 14 and 18. MRD is assessed at 4 timepoints (baseline, week 14, 20 and 32) by flow cytometry and/or molecular analyses. Primary endpoints are the effect of vaccination on MRD status and safety and tolerability of the two vaccination schedules. Secondary endpoints include relapse free, overall survival and immunological response evaluation. Results. As of 28 th July 2021, 19 patients have been enrolled, of which 10 patients have been given at least 4 vaccinations with 25e6 cells/vc and 9 with 50e6 cells/vc. No serious adverse events (AE) or severe AE (grade 3 or higher) related to DCP-001 have been reported. AE's related to DCP-001 are mainly injection site reactions, occurring within 48 hours after intradermal administration. In the 25e6 cells/vc cohort all patients have completed the treatment phase up to week 32, allowing full assessment of MRD response. Three patients have converted to MRD negative, 4 patients relapsed (followed by HSCT for 1 patient), 3 patients remained MRD positive, of which 2 patients underwent HSCT immediately after completion of the full dosing schedule. In this cohort 2 patients eventually died during follow up. Treatment is still ongoing in the 50e6 dose cohort, with thus far one additional MRD conversion reported and two relapses, 3 patients with stable MRD levels, and 3 have no MRD data available yet. Median follow-up of patients in the 25e6 cells/vc cohort was 288 days (range 148 - 546). Median RFS and OS have not yet been reached, but estimated RFS and OS at 12 months is calculated at 57% and 79%, respectively (Figure 1). MRD converted patients after DCP-001 vaccination, showed improved survival, compared to patients without MRD conversion (Figure 2). All 4 patients who converted to MRD negative are still in CR and alive (FU median 423.5 days (range 140 - 546). Immunological monitoring of patients is currently being performed. As previously reported (abstract #168, ASH2020), 3 of 4 evaluable patients show at least 1 or more responses against tumor-associated antigens known to be present in DCP-001 in IFNy ELISPOT assay. Conclusion/discussion. Four patients have shown MRD conversion (3 in the 25e6 dose cohort, and 1 in the 50e6 dose cohort). Six patients remained in complete remission with stable or declining levels of MRD, 6 patients relapsed and for 3 patients no MRD data is available yet. Median RFS and OS have not yet been reached. MRD conversion showed improved relapse free and overall survival. Treatment with DCP-001 is very well tolerated, with limited side effects mainly related to intradermal administration. Immunological analyses for specific tumor-associated antigen responses and general immune profiling are currently being performed. Preliminary data from this study shows that the relapse vaccine DCP-001 is a promising treatment for patients with AML in complete remission but with residual disease aiming to deepen responses and prolong survival. Its excellent safety profile allows for future combination therapy. Figure 1 Figure 1. Disclosures Van de Loosdrecht: Novartis: Consultancy; Alexion: Consultancy; Roche: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Research Funding. Cloos: Takeda: Research Funding; Novartis: Consultancy, Other, Research Funding; Navigate: Patents & Royalties; Merus: Other, Research Funding; Janssen: Research Funding; Helsinn: Other; Genentech: Research Funding; DC-One: Other, Research Funding; Astellas: Speakers Bureau. Platzbecker: AbbVie: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Celgene/BMS: Honoraria; Geron: Honoraria; Takeda: Honoraria. Holderried: Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; MSD: Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Therakos: Other: Travel support; Abbvie: Other: Travel support; Medac: Other: Travel support; Eurocept Pharmaceuticals: Other: Travel support; Janssen: Other: Travel support; Daiichi Sankyo: Other: travel support. Giagounidis: Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. van Zeeburg: Immunicum AB: Current Employment; Kiadis: Ended employment in the past 24 months. Rovers: Immunicum AB: Current Employment. Gjertsen: KinN Therapeutics: Current holder of stock options in a privately-held company; Alden Cancer Therapy: Current holder of stock options in a privately-held company; Pfizer Inc.: Consultancy; BerGenBio: Consultancy; Novartis: Consultancy.


Author(s):  
Yaqi Wang ◽  
Shengxiang Xiao ◽  
Yumin Xia ◽  
Huixia Wang

AbstractSystemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by diverse serological autoantibodies. Anti-dsDNA antibodies are involved in multiple organ damage, especially the kidney, skin, and central nervous system. Anti-dsDNA antibodies play a pivotal role in SLE, and researchers have developed therapeutic strategies targeting these antibodies. Approaches to reduce anti-dsDNA antibodies via B cell targeted biologics against B cell surface antigens, B cell survival factors, or Bruton’s tyrosine kinase have effectively eliminated B cells. However, their non-specific depletion hampers normal immune system functioning and limits the therapeutic benefits. Thus, scientists have attempted anti-dsDNA antibodies or lupus-specific strategies, such as the immature dendritic cell vaccine and immunoadsorption. Recently, synthetic mimic peptides (hCDR1, pCONs, DWEYS, FISLE-412, and ALW) that directly block anti-dsDNA autoantibodies have attracted attention, which could ameliorate lupus, decrease the serological autoantibody titer, reduce the deposition of renal autoantibodies, and improve pathological performance. These potent small peptide molecules are well tolerated, non-toxic, and non-immunogenic, which have demonstrated a benign safety profile and are expected to be hopeful candidates for SLE management. In this review, we clarify the role of anti-dsDNA antibodies in SLE, mainly focus on the current strategies targeting anti-dsDNA antibodies, and discuss their potential clinical value.


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