A preclinical study of cellular immunotherapy redirected by bispecific antibodies in uterine cell lines and primary cancer cells

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 15044-15044
Author(s):  
C. A. Hamilton ◽  
M. M. Zhang ◽  
J. K. Chan ◽  
M. K. Cheung ◽  
S. H. Thorne ◽  
...  
Keyword(s):  
T Cells ◽  
Cytotoxic Activity ◽  
Cancer Cells ◽  
Cell Lines ◽  
Randomized Clinical Trials ◽  
Uterine Cancer ◽  
Bispecific Antibodies ◽  
Cellular Immunotherapy ◽  
Specific Lysis ◽  
Cik Cells

15044 Background: Cytokine induced killer cells (CIKs) are ex-vivo activated and expanded CD8+ natural killer T cells that have been shown to have cytotoxic activity against cancers in randomized clinical trials. We determined the cytotoxic activity of CIK cells against endometrioid and serous papillary (UPSC) uterine cancer cell lines and evaluated the ability of Trastuzumab and Her2xCD3 bispecific antibodies to enhance CIK-mediated cytotoxicity in Her2/neu expressing uterine cancer cells. Methods: The cytotoxicity of CIKs was quantified by 4-hour 51Cr release assays against uterine cell lines HEC-1A (endometrioid) and SPEC-2 (UPSC). Bispecific antibodies against Her2/neu (BSAbHer2) were designed using chemical conjugation methods. Results: Using FACS analysis, we found that the population of CD3+ CD8+ T cells increased from 24% to 56% over 21 days, while the CD3+ CD56+ T cells increased from 7% to 14%. Immunofluorescence microscopy revealed that both cell lines overexpressed Her2/neu. Cytotoxicity assays were performed at effector to target (E:T) ratios of 10:1, 20:1, 40:1 and 100:1 with increasing E:T ratio correlating directly with mean percent specific lysis. At the 100:1 E:T ratio, the mean percent lysis of CIKs against HEC-1A and SPEC-2 cells was 38.8% (±0.21) and 35% (±3.4), respectively. Trastuzumab did not affect the cytotoxic activity of CIKs. However, BSAbHer2 redirection significantly enhanced the cytotoxicity of CIKs against HEC-1A and SPEC-2 cells with a mean percent lysis of 66.3% (±1.0) and 50% (±2.7), respectively. Anti-NKG2D antibodies significantly reduced CIK activity by 49% and 47% in HEC-1A and SPEC-2 cells, respectively. The effects of CIK on advanced uterine cancers were demonstrated using our in vivo bioluminescence imaging system. Conclusion: CIK cells have cytotoxic activity both endometriod and UPSC cell lines. Redirection by BSAbHer2 significantly increased CIK-cell mediated cytotoxicity against Her2/neu expressing cell lines. The mechanism of CIK cytotoxicity appears to be partly mediated by the NKG2D receptor. No significant financial relationships to disclose.

Cellular immunotherapy redirected by bispecific antibodies in primary ovarian cancer cells: A preclinical study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2518-2518
Author(s):  
J. K. Chan ◽  
C. A. Hamilton ◽  
M. K. Cheung ◽  
S. Schulz ◽  
S. H. Thorne ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Randomized Clinical Trials ◽  
Preclinical Study ◽  
Bispecific Antibodies ◽  
Cellular Immunotherapy ◽  
Ovarian Cancer Cells ◽  
Primary Ovarian Cancer ◽  
Cik Cells

2518 Background: Cytokine induced killer cells (CIKs) are ex-vivo activated and expanded CD8+ natural killer T cells that have been shown to have cytotoxic activity against cancers in randomized clinical trials. This preclinical study demonstrates the enhanced effect of CIK killing in primary ovarian carcinoma using bispecific antibodies (BSAbs) and the potential of translating our findings to a clinical trial. Methods: Primary ovarian cancer cells and autologous CIKs were collected and cultured under IRB approval. Cytotoxicity enhancing BSAbs against CA125 (BSAbxCA125) and Her2/neu (BSAbxHer2) were designed using chemical conjugation methods. Tumor cell lysis of ovarian primary ovarian cancer cells was quantified using 51Cr release assays. Anti-NKG2D monoclonal antibodies were used in antibody blocking assays. Using a SCID mouse model of minimal residual disease, tumor progression was monitored using the bioluminescence imaging (BLI) system. Three-color immunofluorescence analysis was performed on pathologic specimens to localize CIK migration to tumor cells. Results: The mean percent lysis with an Effector:Target (E:T) ratio at 100:1 was 22.2% (±2.0) in primary cells in 4-hour killing assays. Redirection with BSAbxCA125 significantly enhanced cytolysis to 65.7% (±0.6). Adding BSAbxHer2 significantly enhanced cytolysis of cell lines to 89.4% (±1.3). Anti-NKG2D antibodies significantly attenuated the CIK activity by 54%. In vivo BLI studies in SCID mice showed that CIK treatment at a 10:1 E:T ratio was well-tolerated and effective in reducing tumor burden by 80% after 21 days post-treatment compared to untreated mice (p<0.0001). Immunofluorescence staining clearly depicted the in vivo infiltration of CIK (CD8+NKG2D+) cells into Her2-expressing tumor targets. Conclusions: Bispecific antibodies effectively enhanced the cytotoxicity of autologous CIK cells against fresh ovarian tumors. Our in vivo studies suggest that CIK cells may ultimately prove to be efficacious immunotheraputic modality in the treatment of resistant ovarian cancer. No significant financial relationships to disclose.

Immunotherapy of Primary Ovarian Cancer Using Autologous Cytokine Induced Killer Cells Retargeted with Bispecific Antibodies: A Preclinical Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2379-2379
Author(s):  
John K. Chan ◽  
Chad A. Hamilton ◽  
Michael K. Cheung ◽  
Mobin Karimi ◽  
Jeanette Baker ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Mouse Model ◽  
Cancer Cells ◽  
Imaging System ◽  
Bispecific Antibodies ◽  
Ovarian Cancer Cells ◽  
Primary Ovarian Cancer ◽  
Cik Cells

Abstract Cytokine induced killer (CIK) cells are ex-vivo activated and expanded CD8+ natural killer T cells that have been shown to have anti-tumor activity. This is the first study exploring cell killing of primary ovarian carcinoma with and without bispecific antibodies (BSAbs). Primary cancer cells and autologous CIK cells were collected from women with epithelial ovarian cancer. BSAbs against CA125 (BSAbxCA125) and Her2 (BSAbxHer2) were developed using chemical heteroconjugation. On FACS analysis, the expansion and stimulation of CIK cells resulted in a significant increase of CD3+CD8+ and CD3+CD56+ T cells. With enhancement by BSAbs, the mean percent lysis in a 51Cr release assay of fresh ovarian cancer cells exposed to autologous CIK cells increased from 22% (±0.3) to 89% (±2.1) at an effector to target ratio (E:T) of 100:1. Anti-NKG2D antibodies significantly attenuated the CIK activity by 57% on primary cells. In a xenograft SCID mouse model, real-time tumor regression and progression was visualized using a non-invasive in vivo bioluminescence imaging system. Four hours after CIK cell injection, we were able to visualize CD8+NKG2D+ CIK cells infiltrating Her2-expressing cancer cells on fluorescence microscopy. Mice that underwent adoptive transfer of CIK cells redirected with BSAbxCA125 (p=0.0002) and BSAbxHer2 (p=0.0002) had a significant reduction in tumor burden and improvement in survival versus those treated with CIK cells alone (p=0.03). BSAbs significantly enhanced the cytotoxicity of CIK cells in primary ovarian cancer cells and in our in vivo mouse model. The mechanism of cytolysis appears to be mediated in part by the NKG2D receptor.

Combining PD-1 blockade with T-cell redirecting bispecific antibodies for solid cancer therapy.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 98-98
Author(s):  
Chien-Hsing Chang ◽  
Yang Wang ◽  
Diane L Rossi ◽  
Rongxiu Li ◽  
Edmund A. Rossi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Cell Lines ◽  
Scid Mice ◽  
Bispecific Antibodies ◽  
Human Pbmcs ◽  
In Vivo Models ◽  
3D Spheroids

98 Background: Bispecific antibodies (bsAbs) for redirecting T cells to cancers have shown promise in both preclinical and clinical studies. However, clinical results have been disappointing in solid cancers. We have applied the DOCK-AND-LOCK method to generate a novel class of trivalent bsAbs, each comprising an anti-CD3 scFv covalently conjugated to a stabilized dimer of different anti-tumor Fabs. Herein we report the characterization of two such constructs, (E1)-3s and (14)-3s, which activate T cells and target Trop-2- and CEACAM5-expressing cancer cells, respectively. Methods: Human breast and colonic cancer cell lines were grown in monolayer cultures or as 3D spheroids for in vitro evaluation. NOD/SCID mice carrying xenografts of MDA-MB-231 (a TNBC line constitutively expressing Trop-2 and PD-L1) were used for in vivo studies. A human PD-1 antagonistic murine hybridoma antibody was subsequently converted to its chimeric form (IMMU-cPD-1). Human PBMCs, or T cells isolated from buffy coats by negative selection, were used as effector cells in cytotoxicity assays. The effect of IMMU-cPD-1 on cancer cells pretreated with IFN-γ to induce the expression of PD-L1 was compared with those not pretreated. Results: (E1)-3s and (14)-3s, in the presence of human T cells, killed target cells grown as monolayers at low picomolar concentrations, with similar potency observed for drug-resistant cells. The antitumor efficacy was demonstrated for (E1)-3s plus human PBMCs in NOD/SCID mice bearing MDA-MB-231, and for human PBMCs combined with (E1)-3s or (14)-3s in 3D spheroids generated from target cell lines to mimic the in vivo behavior and microenvironment of these tumors. Moreover, with the addition of IMMU-cPD-1, the benefit of PD-1 blockade was indicated by increased cell death in 3D spheroids and longer survival of MDA-MB-231-bearing mice. Conclusions: These results highlight the potency of (E1)-3s and (14)-3s as T-cell redirecting bsAbs, emphasize the potential of combining such bsAbs with immune checkpoint inhibitors to improve the therapeutic activity in the immunotherapy of solid cancers, and provide a basis for using 3D spheroids as an alternative to in vivo models for evaluating T-cell functions.

scholarly journals Synthesis and Cytotoxic Activity of Several Novel N-Alkyl-Plinabulin Derivatives With Aryl Group Moieties

2021 ◽  
Vol 16 (4) ◽  
pp. 1934578X2110100
Author(s):  
Pham The Chinh ◽  
Pham Thi Tham ◽  
Duong Huong Quynh ◽  
Nguyen Van Tuyen ◽  
Dinh Thuy Van ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Aldol Condensation ◽  
One Pot ◽  
Aryl Group ◽  
Vascular Disrupting Agents ◽  
Benzaldehyde Derivatives ◽  
Vascular Disrupting

Seven novel N-alkyl-plinabulin derivatives with aryl groups moieties (nitroquinoline, 1,4-dihydroquinoline, 4-methoxybenzene, and 4-chlorobenzene) have been synthesized via aldol condensation and alkylation in one-pot, and tested for their cytotoxicity against 4 cancer cell lines (KB, HepG2, Lu, and MCF7). Compounds ( Z)−3-((6,8-dimethyl-4-oxo-1,4-dihydroquinolin-2-yl)methylene)−6-(( Z)−4-methoxybenzylidene)−1-(prop-2-yn-1-yl)piperazine-2,5-dione (5a), ( Z)−6-(( Z)−4-methoxybenzylidene)−1-(prop-2-yn-1-yl)−3-((1,6,8-trimethyl-4-oxo-1,4-dihydroquinolin-2-yl)methylene)piperazine-2,5-dione (5b), and ( Z)−3-(( Z)−4-chlorobenzylidene)−1,4-dimethyl-6-((8-methyl-4-nitroquinolin-2-yl)methylene)piperazine-2,5-dione (8) showed strong cytotoxicity against 3 of the cancer cells lines (KB, HepG2 and Lu) with IC50 values ranging from 3.04 to 10.62 µM. The quinoline-derived compounds had higher cytotoxic activity than the benzaldehyde derivatives. The successful synthesis of these derivatives offers useful information for the development of more potent vascular disrupting agents based on plinabulin.

scholarly journals Synthesis and Cytotoxic Analysis of Novel Myrtenyl Grafted Pseudo-Peptides Revealed Potential Candidates for Anticancer Therapy

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1911 ◽  
Author(s):  
Odette Concepción ◽  
Julio Belmar ◽  
Alexander F. de la Torre ◽  
Francisco M. Muñiz ◽  
Mariano W. Pertino ◽  
...  
Keyword(s):  
T Cells ◽  
Cytotoxic Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Cd4 T Cells ◽  
Dermal Fibroblast ◽  
Colon Adenocarcinoma ◽  
Cancer Cell Lines ◽  
Biological Properties

Myrtenal is a natural monoterpene isolated from essential oils of several plants and their derivates have shown to have several biological properties including cytotoxicity. The cytotoxic activity of these derivates are being investigated for their antitumor effect leading to the development of potential anticancer agents. In this study, novels Myrtenyl grafted pseudo-peptides were designed, synthesized and functionally characterized as possible therapeutic agents for cancer treatment. Thirteen novel Myrtenyl grafted pseudo-peptides were prepared in high atom economy and efficiency by a classic Ugi-4CR and sequential post-modification. Their structures were confirmed by NMR, and ESI-MS, and its cytotoxic activity was evaluated in three cancer cell lines and primary CD4+ T cells at different proliferative cycles. Our results revealed that some of these compounds showed significant cytotoxicity against human gastric, breast and colon adenocarcinoma cells lines, but not against human dermal fibroblast cell line. Moreover, from the thirteen novel myrtenyl synthesized the compound (1R,5S)-N-{[1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-N-[2-(cyclohexylamino)-2–oxoethyl]-6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-carboxamide (3b) proved to be the best candidate in terms of acceptable EC50, and Emax values in cancer cell lines and at inducing cytotoxicity in CD4+ T cells undergoing active proliferation, without affecting non-proliferating T cells. Overall, the synthesis and characterization of our Myrtenyl derivates revealed novel potential anticancer candidates with selective cytotoxic activity.

scholarly journals TCR β chain–directed bispecific antibodies for the treatment of T cell cancers

2021 ◽  
Vol 13 (584) ◽  
pp. eabd3595 ◽  
Author(s):  
Suman Paul ◽  
Alexander H. Pearlman ◽  
Jacqueline Douglass ◽  
Brian J. Mog ◽  
Emily Han-Chung Hsiue ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cancer Cells ◽  
Cell Cancer ◽  
Bispecific Antibodies ◽  
Target Antigen ◽  
Human T Cell ◽  
Selective Targeting ◽  
Β Chain

Immunotherapies such as chimeric antigen receptor (CAR) T cells and bispecific antibodies redirect healthy T cells to kill cancer cells expressing the target antigen. The pan-B cell antigen–targeting immunotherapies have been remarkably successful in treating B cell malignancies. Such therapies also result in the near-complete loss of healthy B cells, but this depletion is well tolerated by patients. Although analogous targeting of pan-T cell markers could, in theory, help control T cell cancers, the concomitant healthy T cell depletion would result in severe and unacceptable immunosuppression. Thus, therapies directed against T cell cancers require more selective targeting. Here, we describe an approach to target T cell cancers through T cell receptor (TCR) antigens. Each T cell, normal or malignant, expresses a unique TCR β chain generated from 1 of 30 TCR β chain variable gene families (TRBV1 to TRBV30). We hypothesized that bispecific antibodies targeting a single TRBV family member expressed in malignant T cells could promote killing of these cancer cells, while preserving healthy T cells that express any of the other 29 possible TRBV family members. We addressed this hypothesis by demonstrating that bispecific antibodies targeting TRBV5-5 (α-V5) or TRBV12 (α-V12) specifically lyse relevant malignant T cell lines and patient-derived T cell leukemias in vitro. Treatment with these antibodies also resulted in major tumor regressions in mouse models of human T cell cancers. This approach provides an off-the-shelf, T cell cancer selective targeting approach that preserves enough healthy T cells to maintain cellular immunity.

scholarly journals Cyclic-AMP Is an Actionable Novel Regulator of PD-L1 Expression in Untransformed Lymphocytes and Diffuse Large B Cell Lymphomas

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3962-3962
Author(s):  
Binu Sasi ◽  
Zhijun Qiu ◽  
Shoulei Jiang ◽  
An-Ping Lin ◽  
Ricardo Aguiar
Keyword(s):  
T Cells ◽  
Cyclic Amp ◽  
B Cell ◽  
Cancer Cells ◽  
Cell Lines ◽  
Immune Cells ◽  
Checkpoint Inhibitors ◽  
Autocrine Loop ◽  
Large B Cell ◽  
Stat Pathway

Antigen-specific T lymphocytes can recognize and eliminate aberrant cells. Cancer cells halt this process by hijacking a system of immune checkpoints, the programmed cell death 1 (PD-1) and its ligands (PD-L1/2) pathway, which physiologically regulates the quantity and activity of T cells, establishing peripheral T cell tolerance and limiting tissue damage. PD-L1-expressing cancer cells interact with and inhibit PD-1 positive T cells, thus abrogating anti-cancer immunity, which can be restored by checkpoint inhibitors (CPI). Improved understanding of the regulation of PD-L1 expression will shed further light on how cancer cells escape immune surveillance, and it may help in the design of combinatorial therapeutic strategies that expand the activity of CPI. Oncogenes (e.g., MYC, STAT3, HIF1 and NF-KB) have been shown to directly induce PD-L1 transcription. In addition, pro-inflammatory cytokines, notably IFN-γ, via the JAK/STAT pathway, also increase PD-L1 expression, an intuitive counteracting regulatory axis that prevents unchecked inflammation and auto-immunity. The second messenger cyclic-AMP (cAMP) is a classical mediator of anti-inflammatory and immunosuppressive inputs. However, its putative role in PD-L1 regulation is unknown. Addressing this knowledge gap is especially relevant because this signaling node can be modulated with a class of FDA-approved agents, the phosphodiesterase 4 (PDE4) inhibitors. We have recently reviewed the pleiotropic roles that cAMP/PDE4 plays in diffuse large B-cell lymphoma (DLBCL) biology (BloodPMID: 27756749). Thus, to examine if cAMP modulates PD-L1 expression, we first used DLBCL cell lines (n=10). Raising the levels of intracellular cAMP readily induced PD-L1 expression (measured by WB and FACS) in ABC-DLBCLs but not in GCB-DLBCLs. This cAMP-mediated induction of PD-L1 occurred also at RNA level; however, using reporter assays we found that the canonical cAMP-PKA-CREB pathway does not directly activate the PD-L1 promoter. The immune modulatory activity of cAMP is mediated, at least in part, by transcriptional activation/secretion of cytokines. Thus, we considered that cAMP induction of PD-L1 in DLBCL may be driven by an autocrine loop. In agreement with this idea, cAMP promoted JAK/STAT activation and culturing DLBCL cell lines in conditioned media (CM) from cAMP-high models induced PD-L1 expression. These assays pointed to secreted factor(s) as intermediaries in the cAMP/PD-L1 axis. Therefore, we screened a panel of 105 cytokines to identify those secreted by DLBCL cell lines following cAMP up-modulation - in most models, we detected a significant cAMP-driven increase in IL-6, IL-8, IL-10 and IL-1α secretion. For validation, we focused on IL-10 because this was the most commonly cAMP-induced cytokine across the DLBCL models. We found that recombinant IL-10 induced PD-L1, albeit this induction was significantly less marked than that observed following an increase in intra-cellular cAMP. Concordantly, antibody-based blocking of the IL-10 signals, and pharmacologically inhibiting the JAK/STAT pathway, only partially abrogated the cAMP-mediated induction of PD-L1. We concluded that IL-10 and JAK/STAT signals relay part, but not all, of the cAMP effects on PD-L1 expression in DLBCL. Next, we utilized the Pde4b null mouse model to examine if these observations were present in an organismal level and in non-immortalized immune cells. In these assays, spleens of Pde4b WT, +/- and -/- mice (8-16 weeks old, male and female, n=8) were collected and analyzed by WB and FACS. Spleen cells from Pde4b deficient mice had markedly higher expression of PD-L1 (WB). By FACS, we found that the increase in PDL1 expression in Pde4b null mice derived from T cells, B cells, but from the smaller non-B/T cell population (CD19/CD3 negative). Finally, we found that the PDE4 inhibitor roflumilast used as a single agent in vitro robustly induced PD-L1 expression in DLBCL cell lines. In summary, we identified cAMP as an "actionable" novel regulator of PD-L1 expression in normal and malignant immune cells. Mechanistically, cAMP drives an autocrine loop enacted by cytokines and transduced in part by JAK/STAT. This finding supports the clinical testing of roflumilast to induce PD-L1 expression, a strategy that may improve the activity of checkpoint inhibitors in DLBCL and related tumor types. Disclosures No relevant conflicts of interest to declare.

Epigenetic modulation combined with PD-1/PD-L1 blockade enhances immunotherapy based on MAGE-A11 antigen-specific CD8+T cells against esophageal carcinoma

2020 ◽  
Vol 41 (7) ◽  
pp. 894-903
Author(s):  
Yunyan Wu ◽  
Meixiang Sang ◽  
Fei Liu ◽  
Jiandong Zhang ◽  
Weijing Li ◽  
...  
Keyword(s):  
T Cells ◽  
Esophageal Cancer ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cd8 T Cells ◽  
Dna Methyltransferase ◽  
Tumor Cell Lines ◽  
Epigenetic Modulation ◽  
Esophageal Cancer Cells

Abstract Cancer testis antigens (CTAs) are promising targets for T cell-based immunotherapy and studies have shown that certain CT genes are epigenetically depressed in cancer cells through DNA demethylation. Melanoma-associated antigen A11 (MAGE-A11) is a CTA that is frequently expressed in esophageal cancer and is correlated with a poor esophageal cancer prognosis. Consequently, MAGE-A11 is a potential immunotherapy target. In this study, we evaluated MAGE-A11 expression in esophageal cancer cells and found that it was downregulated in several tumor cell lines, which restricted the effect of immunotherapy. Additionally, the specific recognition and lytic potential of cytotoxic T lymphocytes (CTLs) derived from the MAGE-A11 was determined. Specific CTLs could kill esophageal cancer cells expressing MAGE-A11 but rarely lysed MAGE-A11-negative tumor cells. Therefore, induction of MAGE-A11 expression is critical for CTLs recognition and lysis of esophageal cancer cells. Treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine increased MAGE-A11 expression in esophageal cancer cells and subsequently enhanced the cytotoxicity of MAGE-A11-specific CD8+T cells against cancer cell lines. Furthermore, we found that PD-L1 expression in esophageal cancer cells affected the antitumor function of CTLs. programmed death-1 (PD-1)/PD-L1 blockade could increase the specific CTL-induced lysis of HLA-A2+/MAGE-A11+ tumor cell lines treated with 5-aza-2′-deoxycytidine. These findings indicate that the treatment of tumor cells with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine augments MAGE-A11 expression in esophageal cancer cells. The combination of epigenetic modulation by 5-aza-2′-deoxycytidine and PD-1/PD-L1 blockade may be useful for T cell-based immunotherapy against esophageal cancer.

scholarly journals Discovery Strategies to Maximize the Clinical Potential of T-Cell Engaging Antibodies for the Treatment of Solid Tumors

Antibodies ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 65
Author(s):  
Vladimir Voynov ◽  
Paul J. Adam ◽  
Andrew E. Nixon ◽  
Justin M. Scheer
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Clinical Data ◽  
Solid Tumor ◽  
Clinical Studies ◽  
Mode Of Action ◽  
Cytotoxic T Cells ◽  
Molecular Structures ◽  
Bispecific Antibodies

T-cell Engaging bispecific antibodies (TcEs) that can re-direct cytotoxic T-cells to kill cancer cells have been validated in clinical studies. To date, the clinical success with these agents has mainly been seen in hematologic tumor indications. However, an increasing number of TcEs are currently being developed to exploit the potent mode-of-action to treat solid tumor indications, which is more challenging in terms of tumor-cell accessibility and the complexity of the tumor microenvironment (TME). Of particular interest is the potential of TcEs as an immunotherapeutic approach for the treatment of non-immunogenic (often referred to as cold) tumors that do not respond to checkpoint inhibitors such as programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) antibodies. This has led to considerable discovery efforts for, firstly, the identification of tumor selective targeting approaches that can safely re-direct cytotoxic T-cells to cancer cells, and, secondly, bispecific antibodies and their derivatives with drug-like properties that promote a potent cytolytic synapse between T-cells and tumor cells, and in the most advanced TcEs, have IgG-like pharmacokinetics for dosing convenience. Based on encouraging pre-clinical data, a growing number of TcEs against a broad range of targets, and using an array of different molecular structures have entered clinical studies for solid tumor indications, and the first clinical data is beginning to emerge. This review outlines the different approaches that have been taken to date in addressing the challenges of exploiting the TcE mode-of-action for a broad range of solid indications, as well as opportunities for future discovery potential.

scholarly journals Sublethal Radiation Affects Antigen Processing and Presentation Genes to Enhance Immunogenicity of Cancer Cells

2020 ◽  
Vol 21 (7) ◽  
pp. 2573 ◽  
Author(s):  
Achamaporn Punnanitinont ◽  
Eric D. Kannisto ◽  
Junko Matsuzaki ◽  
Kunle Odunsi ◽  
Sai Yendamuri ◽  
...  
Keyword(s):  
New York ◽  
T Cells ◽  
Cancer Cells ◽  
Cell Lines ◽  
Antigen Processing ◽  
Tumor Antigens ◽  
T Cell Response ◽  
Live Cells ◽  
X Rays ◽  
Antigen Processing And Presentation

While immunotherapy in cancer is designed to stimulate effector T cell response, tumor-associated antigens have to be presented on malignant cells at a sufficient level for recognition of cancer by T cells. Recent studies suggest that radiotherapy enhances the anti-cancer immune response and also improves the efficacy of immunotherapy. To understand the molecular basis of such observations, we examined the effect of ionizing X-rays on tumor antigens and their presentation in a set of nine human cell lines representing cancers of the esophagus, lung, and head and neck. A single dose of 7.5 or 15 Gy radiation enhanced the New York esophageal squamous cell carcinoma 1 (NY-ESO-1) tumor-antigen-mediated recognition of cancer cells by NY-ESO-1-specific CD8+ T cells. Irradiation led to significant enlargement of live cells after four days, and microscopy and flow cytometry revealed multinucleation and polyploidy in the cells because of dysregulated mitosis, which was also revealed in RNA-sequencing-based transcriptome profiles of cells. Transcriptome analyses also showed that while radiation had no universal effect on genes encoding tumor antigens, it upregulated the expression of numerous genes involved in antigen processing and presentation pathways in all cell lines. This effect may explain the immunostimulatory role of cancer radiotherapy.

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