Biological Therapy of Hematologic Malignancies: Toward a Chemotherapy- free Era

2019 ◽  
Vol 26 (6) ◽  
pp. 1002-1018 ◽  
Author(s):  
Pavel Klener Jr ◽  
Tomas Etrych ◽  
Pavel Klener
Keyword(s):  
Monoclonal Antibodies ◽  
T Cell ◽  
Cancer Biology ◽  
Checkpoint Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Hematologic Malignancies ◽  
Targeted Agents ◽  
Multi Agent ◽  
Therapeutic Monoclonal Antibodies

:Less than 70 years ago, the vast majority of hematologic malignancies were untreatable diseases with fatal prognoses. The development of modern chemotherapy agents, which had begun after the Second World War, was markedly accelerated by the discovery of the structure of DNA and its role in cancer biology and tumor cell division. The path travelled from the first temporary remissions observed in children with acute lymphoblastic leukemia treated with single-agent antimetabolites until the first cures achieved by multi-agent chemotherapy regimens was incredibly short. Despite great successes, however, conventional genotoxic cytostatics suffered from an inherently narrow therapeutic index and extensive toxicity, which in many instances limited their clinical utilization. In the last decade of the 20th century, increasing knowledge on the biology of certain malignancies resulted in the conception and development of first molecularly targeted agents designed to inhibit specific druggable molecules involved in the survival of cancer cells. Advances in technology and genetic engineering enabled the production of structurally complex anticancer macromolecules called biologicals, including therapeutic monoclonal antibodies, antibody-drug conjugates and antibody fragments. The development of drug delivery systems (DDSs), in which conventional drugs were attached to various types of carriers including nanoparticles, liposomes or biodegradable polymers, represented an alternative approach to the development of new anticancer agents. Despite the fact that the antitumor activity of drugs attached to DDSs was not fundamentally different, the improved pharmacokinetic profiles, decreased toxic side effects and significantly increased therapeutic indexes resulted in their enhanced antitumor efficacy compared to conventional (unbound) drugs.:Approval of the first immune checkpoint inhibitor for the treatment of cancer in 2011 initiated the era of cancer immunotherapy. Checkpoint inhibitors, bispecific T-cell engagers, adoptive T-cell approaches and cancer vaccines have joined the platform so far, represented mainly by recombinant cytokines, therapeutic monoclonal antibodies and immunomodulatory agents. In specific clinical indications, conventional drugs have already been supplanted by multi-agent, chemotherapy-free regimens comprising diverse immunotherapy and/or targeted agents. The very distinct mechanisms of the anticancer activity of new immunotherapy approaches not only call for novel response criteria, but might also change fundamental treatment paradigms of certain types of hematologic malignancies in the near future.

scholarly journals Immunotherapy in hematologic malignancies

2019 ◽  
Vol 27 (S2) ◽  
Author(s):  
R.R. Kansara ◽  
C. Speziali
Keyword(s):  
Monoclonal Antibody ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Hematologic Malignancies ◽  
Immune Checkpoints ◽  
Hematologic Neoplasms

The management of hematologic malignancies has traditionally relied on chemotherapy regimens, many of which are still in use today. However, with advancements in the knowledge of tumour pathophysiology, therapies are continually evolving. Monoclonal antibodies against specific targets on tumour cells are now widely used to treat hematologic malignancies, either in combination with chemotherapy or as single agents. Rituximab, a monoclonal antibody against the CD20 antigen, is a good example of successful monoclonal antibody therapy that has improved outcomes for patients with B cell non-Hodgkin lymphomas. Monoclonal antibodies are now being used against the immune checkpoints that function to inhibit T cell activation and subsequent tumour eradication by those cytotoxic T cells. Such therapies enhance T cell–mediated tumour eradication and are widely successful in treating patients with solid tumours such as malignant melanoma. Now, they are slowly finding their place in the management of hematologic neoplasms. Even though, currently, immune checkpoint inhibitors are used for relapsed or refractory hematologic neoplasms, trials are ongoing to evaluate their role in frontline treatment. Our review focuses on the current use of immunotherapies in various hematologic malignancies.

Targeting Solid Tumors with Bispecific T Cell Engager Immune Therapy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Tara Arvedson ◽  
Julie M. Bailis ◽  
Carolyn D. Britten ◽  
Matthias Klinger ◽  
Dirk Nagorsen ◽  
...  
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
Cancer Biology ◽  
Lymphoblastic Leukemia ◽  
Immune Therapy ◽  
Hematologic Malignancies ◽  
Annual Review ◽  
Publication Date ◽  
Immunosuppressive Tumor Microenvironment ◽  
The Impact

T cell engagers (TCEs) are targeted immunotherapies that have emerged as a promising treatment to redirect effector T cells for tumor cell killing. The strong therapeutic value of TCEs, established by the approval of blinatumomab for the treatment of B cell precursor acute lymphoblastic leukemia, has expanded to include other hematologic malignancies, as well as some solid tumors. Successful clinical development of TCEs in solid tumors has proven challenging, as it requires additional considerations such as the selectivity of target expression, tumor accessibility, and the impact of the immunosuppressive tumor microenvironment. In this review, we provide a brief history of blinatumomab, summarize learnings from TCEs in hematologic malignancies, and highlight results from recent TCE trials in solid tumors. Additionally, we examine approaches to improve the efficacy and safety of TCEs in solid tumors, including therapeutic combinations to increase the depth and durability of response. Expected final online publication date for the Annual Review of Cancer Biology, Volume 6 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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 411 Novel intratumoral agent, INT230–6 induces cancer cell death, increases tumor infiltrates and results in durable benefit alone or in combination with pembrolizumab in refractory patients

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A436-A436
Author(s):  
Anthony El-Khoueiry ◽  
Jacob Thomas ◽  
Anthony Olszanski ◽  
Nilofer Azad ◽  
Lewis Bender ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Cancer Cells ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Single Agent ◽  
Systemic Exposure ◽  
Systemic Circulation ◽  
Cancer Center ◽  
Advanced Malignancy

BackgroundINT230-6 is a novel formulation of cisplatin and vinblastine with an amphiphilic cell penetration enhancer that has been shown to enhance dispersion of the drug throughout tumors and allow diffusion into cells when given intratumorally. In preclinical models, INT230-6 has resulted in cell death, dendritic cell influx, antigen presentation and T-cell engagement with strong synergy when combined with checkpoint inhibitorsMethodsThis phase 1/2 study evaluated Q2week injections of INT230-6 x 5 dosed by tumor volume alone or with 200 mg pembrolizumab IV Q3 weeks. Eligble patients had any advanced malignancy refractory to standard therapy with an injectable tumor.ResultsSixty subjects (median 3 prior therapies (range 0–10)) were enrolled (53 monotherapy, 7 combo). Median age was 60 (42–85). 19 different cancer types were accrued with breast cancer and sarcoma being the most frequent. Over 200 deep tumor injections were administered at doses of up to 172 ml of INT230-6 (86 mg of CIS, 17 mg of Vin). PK analysis revealed <5% of the drugs were measured in systemic circulation, indicative of minimal systemic exposure. There was no dose limiting toxicity. The most frequent monotherapy drug related AE’s reported were: injection-site pain 58%, nausea 37%, fatigue 33%, and vomiting 27% with only 18% of subjects experiencing a grade 3 AE (no grade 4 or 5). Rates were comparable for the single agent INT230-6 and the combination with pembrolizumab. In the overall monotherapy cohort, patients completing all 5 doses of INT230-6 over 56 days (n=16), the median overall survival has not yet been reached. after a median followup of 408 days. In the 5 evaluable patients who received the pembrolizumab combination, the median TTP has not been reached with a median follow up of 6 mo. Paired biopsies (pre, 1 month) were available in 10 monotherapy patients and revealed a median of 63% reduction in viable cancer cells on H&E (30% had no viable cancer) that was also associated with qualitative decreases in Ki67, increases of CD4 and CD8 T-cells and reduction in FoxP3 Tregs. Despite receiving only 2 month of monotherapy, short half lives of the active agents, and no subsequent therapies, 8 injected tumors continued to regress past 1 year.ConclusionsINT230-6 is well tolerated when administered intratumorally alone or in combination with pembrolizumab. Pharmacodynamic assessments provides proof of concept that this drug can reduce viable cancer cells and increases CD4/CD8 T-cell infiltrates leading to durable clinical benefit off treatment.Trial RegistrationNCT 03058289Ethics ApprovalThe study was approved by USC, Princess Margaret Cancer Center, Fox Chase, UMass, Columbia, and Johns Hopkins Institution’s Ethics BoardConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal

scholarly journals Therapeutic Monoclonal Antibodies and Antibody Products: Current Practices and Development in Multiple Myeloma

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 15 ◽  
Author(s):  
Francesca Bonello ◽  
Roberto Mina ◽  
Mario Boccadoro ◽  
Francesca Gay
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
Plasma Cells ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Promising Target ◽  
Therapeutic Monoclonal Antibodies ◽  
Antibody Drug

Immunotherapy is the latest innovation for the treatment of multiple myeloma (MM). Monoclonal antibodies (mAbs) entered the clinical practice and are under evaluation in clinical trials. MAbs can target highly selective and specific antigens on the cell surface of MM cells causing cell death (CD38 and CS1), convey specific cytotoxic drugs (antibody-drug conjugates), remove the breaks of the immune system (programmed death 1 (PD-1) and PD-ligand 1/2 (L1/L2) axis), or boost it against myeloma cells (bi-specific mAbs and T cell engagers). Two mAbs have been approved for the treatment of MM: the anti-CD38 daratumumab for newly-diagnosed and relapsed/refractory patients and the anti-CS1 elotuzumab in the relapse setting. These compounds are under investigation in clinical trials to explore their synergy with other anti-MM regimens, both in the front-line and relapse settings. Other antibodies targeting various antigens are under evaluation. B cell maturation antigens (BCMAs), selectively expressed on plasma cells, emerged as a promising target and several compounds targeting it have been developed. Encouraging results have been reported with antibody drug conjugates (e.g., GSK2857916) and bispecific T cell engagers (BiTEs®), including AMG420, which re-directs T cell-mediated cytotoxicity against MM cells. Here, we present an overview on mAbs currently approved for the treatment of MM and promising compounds under investigation.

scholarly journals Deletion of Pten in CD45-expressing cells leads to development of T-cell lymphoblastic lymphoma but not myeloid malignancies

Blood ◽  
2016 ◽  
Vol 127 (15) ◽  
pp. 1907-1911 ◽  
Author(s):  
Cristina Mirantes ◽  
Maria Alba Dosil ◽  
David Hills ◽  
Jian Yang ◽  
Núria Eritja ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Mouse Model ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Cells ◽  
Hematologic Malignancies ◽  
Lymphoblastic Lymphoma ◽  
Key Points ◽  
Pten Deletion ◽  
Cell Acute Lymphoblastic Leukemia

Key Points CD45-driven expression of Cre generates the first mouse model that allows specific and exclusive deletion of Pten in hematopoietic cells. Pten deletion in CD45-expressing cells causes T-cell acute lymphoblastic leukemia, but no other hematologic malignancies.

The Combination Of Hypomethylating Agents and Histone Deacetylase Inhibitors(HDACi) Are Synergistically Cytotoxic and Reverse The Malignant Phenotype In Preclinical Models Of T-Cell Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 646-646 ◽  
Author(s):  
Owen A. O'Connor ◽  
Enrica Marchi ◽  
Kelly Zullo ◽  
Luigi Scotto ◽  
Jennifer E. Amengual ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Board Of Directors ◽  
Cell Lines ◽  
Single Agent ◽  
Hematologic Malignancies ◽  
Advisory Committees ◽  
Methylation Array ◽  
Simultaneous Exposure ◽  
The Mean

Abstract Both HDAC inhibitors (HDACIs) and DNA methyltransferase inhibitors (DNMTIs) are known to influence global expression patterns in hematologic malignancies. Little is known about the combination of these two drug classes in lymphoid malignancies. HDACIs have marked single agent activity in the T- cell lymphomas (TCL), although the mechanism of action is not well defined. DNMTIs affect cytosine methylation of genomic DNA and have activity mainly restricted to the myeloid derived hematologic malignancies. The single agent efficacy and synergistic interaction of a panel of HDACIs (panobinostat, belinostat, romidepsin and vorinostat) and DNMTIs (decitabine (DEC), 5-azacytadine (5-AZA)) was evaluated in models of TCL. The molecular basis for the synergistic effect of HDACIs and DNMTIs was evaluated by gene expression profiling (GEP) and CpG methylation CTCL. Single agent concentration and time effect relationships were generated for 2 CTCL (HH, H9) and 2 T-ALL (P12, PF382) cell lines. Romidepsin and belinostat were the most potent HDACIs with the mean 48 hour IC50 of 8.8 nM (range 1.7-2.7 nM) and 85 nM (range 36-136 nM), respectively. Cell viability was not affected by treatment with DEC or 5-AZA at 24 and 48 hours at concentrations as high as 20 μM. Reduction in viability was first demonstrated after 72 hours of exposure to DEC, with the mean IC50 of 14.8 μM (range 0.4 μM- >20uM). Simultaneous exposure of combinations of DEC plus romidepsin or DEC plus belinostat at their IC10, IC20, and IC50 produced marked synergy in all TCL derived cell lines. Simultaneous exposure of DEC plus romidepsin demonstrated the deepest synergy at 72 hours with synergy coefficients in the range of 0.3. Cells treated with the combination of DEC plus romidepsin also demonstrated significant induction of apoptosis as evaluated by annexinV/propridium iodide via FACS analysis and an increase in acetylated histone 3 by immunoblot. The in vivo activity of the combination of DEC plus belinostat was investigated in a xenograft model of CTCL using HH, the most resistant TCL derived cell line. Mice were treated with DEC 1.5 mg/kg (day 29, 33, 35, 37, 39, 41, 43) and/or belinostat 100 mg/kg (day 29-day 47). The combination mouse cohort demonstrated statistically significant tumor growth delay compared to DEC alone (p=0.002) and belinostat alone (p=0.001). The interaction of DEC and romidepsin was analyzed by GEP and methylation array. Interestingly, the baseline malignant phenotype seen in the CTCL cell-lines was reversed. A significant down-regulation of genes involved in biosynthetic pathways including protein and lipid synthesis, and a significant up-regulation of genes responsible for cell cycle arrest were seen. The vast majority (114/138; 92%) of genes modulated by the single agents were similarly modulated by the combination. However, the latter induced a further significant change in the transcriptome, affecting an additional 390 genes. Similarly, methylation array data was analyzed following treatment of these drugs alone and in combination. DEC induced de-methylation of 190 different gene regions corresponding to 175 genes and an additional 335 loci. Interestingly, when combined with romidepsin the number of demethylated gene regions decreased to 85 corresponding to 79 genes, 78 of which were common with DEC and 148 additional loci. The comparison of gene expression and methylation demonstrated a significant inverse relationship (R2 = 0.657) with genes found to be differentially expressed in GEP and methylation analysis. (Figure 1)Figure 1Summary of gene expression and methylation analysis.Figure 1. Summary of gene expression and methylation analysis. These data support the observation that DNMTIs in combination with HDACIs produces significant synergistic activity in models of TCL. Further evaluation of the mechanism of action with DNMTIs in combination with HDACIs is ongoing, and a clinical trial of the combination is now open. Disclosures: O'Connor: Celgene Pharmaceuticals: Consultancy; Spectrum Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Allos Therapeutics: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Hypomethylating Agents in T-cell lymphoma. Amengual:Acetylon Pharmacueticals, INC: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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