Combination epigenetic and immunotherapy overcomes resistance to monoclonal antibodies in hematologic malignancies: A new therapeutic approach

2016 ◽  
Vol 44 (3) ◽  
pp. 157-160 ◽  
Author(s):  
Elliot M. Epner ◽  
Bikramajit Singh Saroya ◽  
Zainul S. Hasanali ◽  
Thomas P. Loughran
Keyword(s):  
Monoclonal Antibodies ◽  
Therapeutic Approach ◽  
Hematologic Malignancies

Therapeutic Monoclonal Antibodies in Clinical Practice against Cancer

2020 ◽  
Vol 20 (16) ◽  
pp. 1895-1907
Author(s):  
Navgeet Kaur ◽  
Anju Goyal ◽  
Rakesh K. Sindhu
Keyword(s):  
Monoclonal Antibody ◽  
Monoclonal Antibodies ◽  
Clinical Practice ◽  
Therapeutic Agent ◽  
Hematologic Malignancies ◽  
Immune Checkpoints ◽  
Malignant Cells ◽  
Main Target ◽  
Therapeutic Monoclonal Antibodies ◽  
Cancerous Cells

The importance of monoclonal antibodies in oncology has increased drastically following the discovery of Milstein and Kohler. Since the first approval of the monoclonal antibody, i.e. Rituximab in 1997 by the FDA, there was a decline in further applications but this number has significantly increased over the last three decades for various therapeutic applications due to the lesser side effects in comparison to the traditional chemotherapy methods. Presently, numerous monoclonal antibodies have been approved and many are in queue for approval as a strong therapeutic agent for treating hematologic malignancies and solid tumors. The main target checkpoints for the monoclonal antibodies against cancer cells include EGFR, VEGF, CD and tyrosine kinase which are overexpressed in malignant cells. Other immune checkpoints like CTLA-4, PD-1 and PD-1 receptors targeted by the recently developed antibodies increase the capability of the immune system in destroying the cancerous cells. Here, in this review, the mechanism of action, uses and target points of the approved mAbs against cancer have been summarized.

scholarly journals Nuclear factor-KappaB modulation as a therapeutic approach in hematologic malignancies

Cancer ◽  
2004 ◽  
Vol 100 (8) ◽  
pp. 1578-1589 ◽  
Author(s):  
Amit Panwalkar ◽  
Srdan Verstovsek ◽  
Francis Giles
Keyword(s):  
Therapeutic Approach ◽  
Hematologic Malignancies ◽  
Nuclear Factor Kappab ◽  
Nuclear Factor

scholarly journals The Immune Response to Tumors as a Tool toward Immunotherapy

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
F. Pandolfi ◽  
R. Cianci ◽  
D. Pagliari ◽  
F. Casciano ◽  
C. Bagalà ◽  
...  
Keyword(s):  
Immune Response ◽  
Monoclonal Antibodies ◽  
Cancer Colorectal ◽  
Immune Cell ◽  
Cytotoxic T Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Hematologic Malignancies ◽  
The Novel ◽  
Infiltrating Lymphocytes

Until recently cancer medical therapy was limited to chemotherapy that could not differentiate cancer cells from normal cells. More recently with the remarkable mushroom of immunology, newer tools became available, resulting in the novel possibility to attack cancer with the specificity of the immune system. Herein we will review some of the recent achievement of immunotherapy in such aggressive cancers as melanoma, prostatic cancer, colorectal carcinoma, and hematologic malignancies. Immunotherapy of tumors has developed several techniques: immune cell transfer, vaccines, immunobiological molecules such as monoclonal antibodies that improve the immune responses to tumors. This can be achieved by blocking pathways limiting the immune response, such as CTLA-4 or Tregs. Immunotherapy may also use cytokines especially proinflammatory cytokines to enhance the activity of cytotoxic T cells (CTLs) derived from tumor infiltrating lymphocytes (TILs). The role of newly discovered cytokines remains to be investigated. Alternatively, an other mechanism consists in enhancing the expression of TAAs on tumor cells. Finally, monoclonal antibodies may be used to target oncogenes.

Phase I Studies in Hematologic Malignancy: 20-Year Experience from Cancer Therapy Evaluation Program (CTEP) at National Cancer Institute/National Institutes of Health

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 18-18
Author(s):  
Dai Chihara ◽  
Erich P. Huang ◽  
Shanda R. Finnigan ◽  
Lisa M. Cordes ◽  
Nebojsa Skorupan ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Phase I ◽  
Response Rate ◽  
Hematologic Malignancy ◽  
Phase 1 ◽  
Performance Status ◽  
Hematologic Malignancies ◽  
Phase I Studies ◽  
Grade 5 ◽  
Investigational Agents

Background Phase I study is an essential step of drug development to assess safety, but more recently also to investigate initial insights into potential patient therapeutic response. In the last two decades, treatment of hematologic malignancy has changed dramatically from chemotherapy to targeted agents such as monoclonal antibodies, small molecule inhibitors and immunotherapy. We leveraged a large cohort of phase 1 studies to assess trends in toxicity, response and survival outcomes over time. Methods We reviewed the database of all investigator-initiated phase 1 oncology trials treated patients with hematologic malignancies sponsored by CTEP at the NCI between 2000 and 2019. We report the rates of grade 5 toxicity, response to treatment, and survival outcome following enrollment to the trials. Univariate associations of rates of Grade 5 toxicities possibly, probably, or definitely attributable to treatment and response rate with disease type, year of study activation, or whether each type of treatment was administered were assessed through likelihood ratio tests of a generalized linear mixed model. Results Overall, 3,308 patients were treated in 161 trials. Median age of the patients was 61 (range: 0-96) and 61% were male. Acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) was the most common enrolled malignancy diagnosis (N=1,768) followed by lymphoma (N=921), acute lymphoblastic lymphoma (ALL: N=193) and myeloma (N=153). Forty percent of the trials used an investigational agent as a monotherapy, while 60% of the trials used combination treatment. The most commonly used non-chemotherapy investigational agents were monoclonal antibodies and HDAC inhibitors (28 trials each), followed by DNMT inhibitors (18 trials) and proteasome inhibitors (17 trials). Overall, 468 patients died during trials of which 60 were attributed to the treatment (grade 5 toxicity: 1.81%, 95%CI: 1.36-2.27%). There was a trend of higher grade 5 toxicity in patients with AML/MDS (2.43%) compared to patients with lymphoma (0.98%), ALL (1.55%) or myeloma (0.65%) (p=0.066). Treatment with a PD-1 inhibitor was associated with significantly higher risk of grade 5 toxicities (7.14%, 95%CI: 1.95%-12.3%), compared to patients who did not receive a PD-1 inhibitor (1.65%, 95%CI: 1.21%-2.09%) (odds ratio [OR]: 4.93, 95%CI: 1.54-15.8). The deaths mostly occurred in trials combining a PD-1 inhibitor and a CTLA-4 inhibitor (6 death in 77 pts), although the grade 5 toxicity rate did not significantly differ from PD-1 inhibitor monotherapy (1 death in 21 pts). There was no significant difference in grade 5 toxicity among the time periods when trials were activated (Table. 2000-2005 vs 2006-2012 vs 2013-2019). Baseline characteristics associated with higher risk of grade 5 toxicity were age (OR: 1.02 by 1 year increase in age, 95%CI: 1.01-1.04, p=0.007) and performance status ≥2 at enrollment (OR: 1.56, 95%CI: 1.02-2.39, p=0.039). Response assessment was available in 2,404 patients. Overall response rate (ORR) and CR rate (CRR) from all trials were 25.1% (95%CI: 23.3-26.8%) and 14.7% (95%CI: 13.3-16.2%), respectively. The patients with lymphoma experienced significantly higher ORR (42.8%) compared to patients with AML (18.2%), ALL (13.3%) or myeloma (13.3%). There is a significant increase in both ORR and CRR over time (Table. p<0.001), but the trend of change was different in each disease by investigational agents tested during the period. Monoclonal antibodies, iMIDs, CDK inhibitors and BTK inhibitors were non-chemotherapy agents associated with higher response rate. Overall survival (OS) was available in 2,664 patients. The median OS among all patients after enrollment in phase 1 studies was 277 days (95%CI: 245-305 days). Patients with ALL had significantly shorter median OS (86 days) compared to patients with AML/MDS (255 days), lymphoma (289 days) or myeloma (median not reached). Conclusion There has been a significant improvement of ORR in CTEP sponsored phase I studies in the last 20 years. Grade 5 toxicity rate remained low, but higher age and poor performance status were associated with higher risk. Participation in phase I studies should be encouraged in patients with hematologic malignancies. Table Disclosures No relevant conflicts of interest to declare.

Safety and Immunogenicity Of Inactivated Varicella-Zoster Virus Vaccine In Adults With Hematologic Malignancies Receiving Treatment With Anti-CD20 Monoclonal Antibodies

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2290-2290
Author(s):  
Shelly McNeil ◽  
Robert Betts ◽  
Steven Lawrence ◽  
Andrea Velardi ◽  
Eva Kimby ◽  
...  
Keyword(s):  
Immune Response ◽  
Monoclonal Antibodies ◽  
Research Funding ◽  
Hematologic Malignancies ◽  
Employment Equity ◽  
Varicella Zoster ◽  
Cell Responses ◽  
Equity Ownership ◽  
Ifn Γ ◽  
Anti Cd20

Abstract Background Herpes zoster (HZ) incidence is higher in patients with hematologic malignancies (HM) (25-100 cases/1000 person-years) than in the general population (3-5 cases/1000 person-years). This immunocompromised population can experience significant morbidity and occasional mortality from complications associated with reactivation of the varicella-zoster virus (VZV). In general, there is limited data in the literature regarding the effect of anti-CD20 monoclonal antibodies, used in treatment of HM patients, on vaccine-related cell-mediated immune response. Due to the potential negative impact of anti-CD20 monoclonal antibodies on vaccine immunogenicity and efficacy, HM patients receiving anti-CD20 monoclonal antibodies have been excluded from prior inactivated VZV vaccine (inactivated-ZV) studies. This study evaluated the safety and immunogenicity of inactivated-ZV in HM patients receiving anti-CD20 monoclonal antibody therapy. Methods This was an open label, single arm, multicenter Phase I study of a 4-dose inactivated-ZV regimen (∼30 days between each dose) in patients ≥18 years old with HM receiving anti-CD20 monoclonal antibodies either as a single agent or in a combination chemotherapy regimen and not likely to undergo HCT (n=80). Blood samples were collected at baseline prior to dose 1 and 28 days postdose 4 to measure VZV-specific T-cell responses using interferon-gamma enzyme-linked immunospot (IFN-γ ELISPOT). The primary hypothesis was that inactivated-ZV would elicit significant VZV-specific immune responses at ∼28 days postdose 4, with the statistical criterion being that the lower bound of the two-sided 90% confidence interval (CI) on the geometric fold rise (GMFR) be >1.0. All vaccinated patients were evaluated for adverse events (AE), including VZV-like rashes, through 28 days postdose 4. Results The 4-dose inactivated-ZV regimen elicited a statistically significant VZV-specific immune response measured by IFN-γ ELISPOT at 28 days postdose 4 in the per-protocol population (GMFR = 4.34 [90% CI: 3.01, 6.24], p-value <0.001). As the lower bound of the 2-sided 90% CI for GMFR was >1.0, the pre-specified primary immunogenicity success criterion was met. Overall, 85% (68/80) of patients reported ≥1 AEs, 44% (35/80) reported ≥1 injection-site AEs, and 74% (59/80) reported ≥1 systemic AEs. The most common injection-site AEs were pain (32%), erythema (31%), and swelling (26%). The most common systemic AEs were pyrexia (25%) and diarrhea (14%). Twelve patients (15%) experienced serious AEs, including one event determined by the investigator to be vaccine-related (convulsion: day 8 postdose 1). One patient experienced a fatal serious AE (Richter’s transformation to Hodgkin’s disease; day 34 postdose 1) assessed as not vaccine-related by the investigator. In general, the frequencies of AEs did not increase with subsequent doses of vaccine. No inactivated-ZV recipient had a rash that was PCR positive for VZV vaccine strain. Conclusions In adults with HM receiving anti-CD20 monoclonal antibodies, inactivated-ZV was well tolerated and elicited statistically significant VZV-specific T-cell responses ∼28 days postdose 4. Disclosures: McNeil: Merck: investigator Other, Research Funding. Betts:Merck: investigator Other, Research Funding. Lawrence:Merck: investigator Other, Research Funding. Velardi:Merck: investigator Other, Research Funding. Kimby:Merck: investigator Other, Research Funding. Pagnoni:Merck: Employment, Equity Ownership. Stek:Merck: Employment, Equity Ownership. Zhao:Merck: Employment, Equity Ownership. Chan:Merck: Employment, Equity Ownership. Lee:Merck: Employment, Equity Ownership. Parrino:Merck: Employment, Equity Ownership.

scholarly journals Radiolabeled anti-CD45 monoclonal antibodies target lymphohematopoietic tissue in the macaque

Blood ◽  
1991 ◽  
Vol 78 (7) ◽  
pp. 1864-1874 ◽  
Author(s):  
DC Matthews ◽  
FR Appelbaum ◽  
JF Eary ◽  
TE Hui ◽  
DR Fisher ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Monoclonal Antibodies ◽  
Lymph Nodes ◽  
Marrow Transplantation ◽  
Absorbed Dose ◽  
Hematologic Malignancies ◽  
Macaca Nemestrina ◽  
Improve Treatment ◽  
Antibody Uptake ◽  
Relative Specificity

Abstract Despite bone marrow transplantation, many patients with advanced leukemia subsequently relapse. If an additional increment of radiation could be delivered to lymphohematopoietic tissues with relative specificity, the relapse rate may decrease without a marked increase in toxicity. We have examined the biodistribution of two 131I-labeled monoclonal antibodies reactive with the CD45 antigen in Macaca nemestrina. Three animals received 0.5 mg/kg BC8, an IgG1 of low avidity (6 x 10(7) L/mol). Three received 0.5 mg/kg AC8, an IgG2a of moderate avidity (5 x 10(8) L/mol), and two received 4.5 mg/kg AC8. Estimates of radiation absorbed dose demonstrated that these antibodies could deliver up to five times more radiation to lymph nodes, and up to 2.6 times more to bone marrow, than to lung or liver. The higher avidity AC8 antibody at 0.5 mg/kg was cleared more rapidly from blood and resulted in lower antibody uptake in lymph nodes than did BC8 at 0.5 mg/kg. Increasing the dose of AC8 to 4.5 mg/kg resulted in slower blood clearance and higher lymph node uptake. These studies suggest that radiolabeled anti-CD45 antibodies can deliver radiation with relative specificity to lymphohematopoietic tissues. This approach, in combination with marrow transplantation, may improve treatment of hematologic malignancies.

scholarly journals Airway Delivery of Anti-influenza Monoclonal Antibodies Results in Enhanced Antiviral Activities and Enables Broad-Coverage Combination Therapies

2020 ◽  
Vol 94 (22) ◽  
Author(s):  
Adam Vigil ◽  
Natalia Frias-Staheli ◽  
Teresa Carabeo ◽  
Michael Wittekind
Keyword(s):  
Monoclonal Antibodies ◽  
Therapeutic Approach ◽  
Neutralizing Antibodies ◽  
Lethal Dose ◽  
Passive Immunization ◽  
Cost Effective ◽  
Effector Function ◽  
Influenza Viruses ◽  
Apical Side ◽  
Promising Therapeutic Approach

ABSTRACT Effective and reliable anti-influenza treatments are acutely needed and passive immunizations using broadly neutralizing anti-influenza monoclonal antibodies (bNAbs) are a promising emerging approach. Because influenza infections are initiated in and localized to the pulmonary tract, and newly formed viral particles egress from the apical side of the lung epithelium, we compared the effectiveness of hemagglutinin (HA) stalk-binding bNAbs administered through the airway (intranasal or via nebulization) versus the systemic route (intraperitoneal or intravenous). Airway deliveries of various bNAbs were 10- to 50-fold more effective than systemic deliveries of the same bNAbs in treating H1N1, H3N2, B/Victoria-, and B/Yamagata-lineage influenza viral infections in mouse models. The potency of airway-delivered anti-HA bNAbs was highly dependent on antiviral neutralization activity, with little dependence on the effector function of the antibody. In contrast, the effectiveness of systemically delivered anti-HA bNAbs was not dependent on antiviral neutralization, but critically dependent on antibody effector functions. Concurrent administration of a neutralizing/effector function-positive bNAb via the airway and systemic routes showed increased effectiveness. The small amount of airway-delivered bNAbs needed for effective influenza treatment creates the opportunity to combine potent bNAbs with different anti-influenza specificities to generate a cost-effective antiviral therapy that provides broad coverage against all circulating influenza strains infecting humans. A 3 mg/kg dose of the novel triple antibody combination CF-404 (i.e., 1 mg/kg of each component bNAb) delivered to the airway was shown to effectively prevent weight loss and death in mice challenged with ten 50% lethal dose (LD50) inoculums of either H1N1, H3N2, B/Victoria-lineage, or B/Yamagata-lineage influenza viruses. IMPORTANCE Influenza causes widespread illness in humans and can result in morbidity and death, especially in the very young and elderly populations. Because influenza vaccination can be poorly effective some years, and the immune systems of the most susceptible populations are often compromised, passive immunization treatments using broadly neutralizing antibodies is a promising therapeutic approach. However, large amounts of a single antibody are required for effectiveness when delivered through systemic administration (typically intravenous infusion), precluding the feasible dosing of antibody combinations via this route. The significance of our research is the demonstration that effective therapeutic treatments of multiple relevant influenza types (H1N1, H3N2, and B) can be achieved by airway administration of a single combination of relatively small amounts of three anti-influenza antibodies. This advance exploits the discovery that airway delivery is a more potent way of administering anti-influenza antibodies compared to systemic delivery, making this a feasible and cost-effective therapeutic approach.

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