scholarly journals Complete Regression of Metastatic Cervical Cancer After Treatment With Human Papillomavirus–Targeted Tumor-Infiltrating T Cells

2015 ◽  
Vol 33 (14) ◽  
pp. 1543-1550 ◽  
Author(s):  
Sanja Stevanović ◽  
Lindsey M. Draper ◽  
Michelle M. Langhan ◽  
Tracy E. Campbell ◽  
Mei Li Kwong ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
T Cells ◽  
Human Papillomavirus ◽  
Partial Response ◽  
Clinical Response ◽  
Adoptive T Cell Therapy ◽  
Complete Regression ◽  
Single Infusion ◽  
T Cell Therapy ◽  
Platinum Based Chemotherapy

Purpose Metastatic cervical cancer is a prototypical chemotherapy-refractory epithelial malignancy for which better treatments are needed. Adoptive T-cell therapy (ACT) is emerging as a promising cancer treatment, but its study in epithelial malignancies has been limited. This study was conducted to determine if ACT could mediate regression of metastatic cervical cancer. Patients and Methods Patients enrolled onto this protocol were diagnosed with metastatic cervical cancer and had previously received platinum-based chemotherapy or chemoradiotherapy. Patients were treated with a single infusion of tumor-infiltrating T cells selected when possible for human papillomavirus (HPV) E6 and E7 reactivity (HPV-TILs). Cell infusion was preceded by lymphocyte-depleting chemotherapy and was followed by administration of aldesleukin. Results Three of nine patients experienced objective tumor responses (two complete responses and one partial response). The two complete responses were ongoing 22 and 15 months after treatment, respectively. One partial response was 3 months in duration. The HPV reactivity of T cells in the infusion product (as measured by interferon gamma production, enzyme-linked immunospot, and CD137 upregulation assays) correlated positively with clinical response (P = .0238 for all three assays). In addition, the frequency of HPV-reactive T cells in peripheral blood 1 month after treatment was positively associated with clinical response (P = .0238). Conclusion Durable, complete regression of metastatic cervical cancer can occur after a single infusion of HPV-TILs. Exploratory studies suggest a correlation between HPV reactivity of the infusion product and clinical response. Continued investigation of this therapy is warranted.

Phase I/II Study of Marrow Infiltrating Lymphocytes (MILs) Generates Measurable Myeloma-Specific Immunity in the Autologous Stem Cell Transplant (SCT) Setting

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 997-997
Author(s):  
Kimberly Noonan ◽  
Carol A. Huff ◽  
Janice M Davis Sproul ◽  
Mario Victor M Lemas ◽  
Lakshmi Rudraraju ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase I ◽  
Clinical Response ◽  
Peripheral Blood ◽  
Immune Monitoring ◽  
Adoptive T Cell Therapy ◽  
Effector Memory ◽  
Cell Transplant ◽  
T Cell Therapy

Abstract Abstract 997 Adoptive T cell therapy requires the infusion of highly tumor specific T cells capable of trafficking to the tumor site, killing the tumor and persisting over time. MILs (as compared to peripheral blood T cells) possess many of these features (Noonan, Ca, Res. 2006). We here report the initial results from our Phase I/II trial. 22 patients were transplanted with a Melphalan-200. 19 with a CD34-selected product, 1 unselected autologous stem cells and 2 auto-BMT. 12 underwent SCT as initial consolidation and 10 patients with relapsed disease that were heavily pre-treated with an average of 3.2 prior therapies. Mean ISS score was 2.0. Average age was 56 (29–71). MILs were expanded with anti-CD3/CD28 beads for 7 days (avg. fold expansion 48.5 and avg. cell dose 2.8×10e7 CD3/kg). MILs were infused on day +3. Patients in a CR were ineligible for this study. The best clinical response included 6CRs (27%), 10PRs (45%). Autologous GVHD which was observed in 32% of patients, was limited to the skin and required no treatment. Development of this syndome did not correlate with improved clinical outcomes. Lymphoid recovery was rapid with a mean absolute lymphocyte count (ALC) on day 15 of 886 cells/ul. The laboratory immune monitoring studies were only performed in the bone marrow – the disease site and not in the peripheral blood. The percent CD3+ T cells in the BM was 13% at baseline with a CD4:CD8 ratio of 1:3. By day 60, BM T cell reconstitution was complete and showed an inversion of the CD4:8 ratio of 0.39 that persisted through day 360. At baseline, there were more CD4 effector memory (CD4EM) (CD62L−/CD45RO+) than CD4 central memory (CD4CM) (CD62L+/CD45RO+) (43% vs 27%). The CD4CM population peaked on day 60 at 43% and persisted through 1 year, CD4EM remained unchanged, and the CD4Effector decreased from 19.8% to 5.6%. The CD8 subpopulations remained unchanged from pre-SCT to 1 year post-SCT. Treg numbers doubled from harvest to post-SCT consistent with previous studies showing a greater number of Tregs in healthy BM compared to MM-BM. Activated T cells (CD69+) doubled from pre- to post-SCT. IFNγ production in both CD4 and CD8 cells more than doubled compared to pre-SCT and was maintained at 1 year suggesting the persistence of the infused MILs. The immune monitoring in the BM based on clinical responses revealed that patients achieving a CR/PR showed greater CD8 numbers at day +60 compared to stable disease (SD) or progressive disease (PD)(14.5% vs. 7.6%, respectively) and inversion of the CD4/CD8 ratio at 1 year (0.55 vs 1.26). In patients with SD or PD, the immune infiltrate in the BM was characterized by a large numbers of effector and effector-memory T cells and few CD8CM at baseline. CR patients possessed the fewest CD8Effector and the most CD8CM with persistence of CD8CM out to one year. These patients also showed a greater expansion in IFNγ cells as well as a greater amount of IFNγ production at each time point. Importantly, tumor-specific IFNγ production of CD3 cells in the BM was predictive of a clinical response. Patients achieving a CR showed twice the antigen-specific IFNγ production compared to all other groups at day 180 which persisted through 1 year. Analyses of additional immune subsets will be discussed in greater detail. This is the first reported trial utilizing activated MILs as a source of tumor specific T cells. We have demonstrated the ability to effectively expand MILs ex vivo and provide an analysis of the parameters of immune reconstitution demonstrating that the clinical outcome correlated with the robustness of the immune response in the BM. Disclosures: Luznik: Otsuka Pharmaceuticals: Research Funding.

scholarly journals A modular and controllable T cell therapy platform for acute myeloid leukemia

Leukemia ◽  
2021 ◽  
Author(s):  
Mohamed-Reda Benmebarek ◽  
Bruno L. Cadilha ◽  
Monika Herrmann ◽  
Stefanie Lesch ◽  
Saskia Schmitt ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Cell Therapy ◽  
Myeloid Leukemia ◽  
Tumor Antigens ◽  
Adoptive T Cell Therapy ◽  
Single Chain ◽  
T Cell Therapy ◽  
Acute Myeloid

AbstractTargeted T cell therapy is highly effective in disease settings where tumor antigens are uniformly expressed on malignant cells and where off-tumor on-target-associated toxicity is manageable. Although acute myeloid leukemia (AML) has in principle been shown to be a T cell-sensitive disease by the graft-versus-leukemia activity of allogeneic stem cell transplantation, T cell therapy has so far failed in this setting. This is largely due to the lack of target structures both sufficiently selective and uniformly expressed on AML, causing unacceptable myeloid cell toxicity. To address this, we developed a modular and controllable MHC-unrestricted adoptive T cell therapy platform tailored to AML. This platform combines synthetic agonistic receptor (SAR) -transduced T cells with AML-targeting tandem single chain variable fragment (scFv) constructs. Construct exchange allows SAR T cells to be redirected toward alternative targets, a process enabled by the short half-life and controllability of these antibody fragments. Combining SAR-transduced T cells with the scFv constructs resulted in selective killing of CD33+ and CD123+ AML cell lines, as well as of patient-derived AML blasts. Durable responses and persistence of SAR-transduced T cells could also be demonstrated in AML xenograft models. Together these results warrant further translation of this novel platform for AML treatment.

scholarly journals IMMU-31. QUANTITATIVE EVALUATION OF ROUTES OF ADMINISTRATION OF IMMUNOTHERAPEUTIC T CELLS TO ORTHOTOPIC GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii111-ii111
Author(s):  
Lan Hoang-Minh ◽  
Angelie Rivera-Rodriguez ◽  
Fernanda Pohl-Guimarães ◽  
Seth Currlin ◽  
Christina Von Roemeling ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Ex Vivo ◽  
Adoptive T Cell Therapy ◽  
Whole Body ◽  
T Cell Therapy ◽  
Clinical Responses

Abstract SIGNIFICANCE Adoptive T cell therapy (ACT) has emerged as the most effective treatment against advanced malignant melanoma, eliciting remarkable objective clinical responses in up to 75% of patients with refractory metastatic disease, including within the central nervous system. Immunologic surrogate endpoints correlating with treatment outcome have been identified in these patients, with clinical responses being dependent on the migration of transferred T cells to sites of tumor growth. OBJECTIVE We investigated the biodistribution of intravenously or intraventricularly administered T cells in a murine model of glioblastoma at whole body, organ, and cellular levels. METHODS gp100-specific T cells were isolated from the spleens of pmel DsRed transgenic C57BL/6 mice and injected intravenously or intraventricularly, after in vitro expansion and activation, in murine KR158B-Luc-gp100 glioma-bearing mice. To determine transferred T cell spatial distribution, the brain, lymph nodes, heart, lungs, spleen, liver, and kidneys of mice were processed for 3D imaging using light-sheet and multiphoton imaging. ACT T cell quantification in various organs was performed ex vivo using flow cytometry, 2D optical imaging (IVIS), and magnetic particle imaging (MPI) after ferucarbotran nanoparticle transfection of T cells. T cell biodistribution was also assessed in vivo using MPI. RESULTS Following T cell intravenous injection, the spleen, liver, and lungs accounted for more than 90% of transferred T cells; the proportion of DsRed T cells in the brains was found to be very low, hovering below 1%. In contrast, most ACT T cells persisted in the tumor-bearing brains following intraventricular injections. ACT T cells mostly concentrated at the periphery of tumor masses and in proximity to blood vessels. CONCLUSIONS The success of ACT immunotherapy for brain tumors requires optimization of delivery route, dosing regimen, and enhancement of tumor-specific lymphocyte trafficking and effector functions to achieve maximal penetration and persistence at sites of invasive tumor growth.

scholarly journals Engineering adoptive T cell therapy to co-opt Fas ligand-mediated death signaling in ovarian cancer enhances therapeutic efficacy

2021 ◽  
Author(s):  
Kristin G. Anderson ◽  
Shannon K. Oda ◽  
Breanna M. Bates ◽  
Madison G. Burnett ◽  
Magdalia Rodgers Suarez ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Cell Therapy ◽  
Tumor Vasculature ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy ◽  
Tumor Bearing ◽  
Infiltrating Lymphocytes

Background: In the U.S., more than 50% of ovarian cancer patients die within 5 years of diagnosis, highlighting the need for innovations such as engineered T cell therapies. Mesothelin (Msln) is an attractive immunotherapy target for this cancer, as it is overexpressed by the tumor and contributes to malignant and invasive phenotypes, making antigen loss disadvantageous to the tumor. We previously showed that adoptively transferred T cells engineered to be Msln-specific (TCR1045) preferentially accumulate within established ovarian tumors, delay tumor growth and significantly prolong survival in the ID8VEGF mouse model. However, T cell persistence and anti-tumor activity were not sustained, and we and others have previously detected FasL in the tumor vasculature and the tumor microenvironment (TME) of human and murine ovarian cancers, which can induce apoptosis in infiltrating lymphocytes expressing Fas receptor (Fas). Methods: To concurrently overcome this mechanism for potential immune evasion and enhance T cell responses, we generated an immunomodulatory fusion protein (IFP) containing the Fas extracellular binding domain fused to a 4-1BB co-stimulatory domain, rather than the natural death domain. T cells engineered to express TCR1045 alone or in combination with the IFP were transferred into ID8VEGF-tumor bearing mice and evaluated for persistence, proliferation, anti-tumor cytokine production, and therapeutic efficacy. Results: Relative to T cells modified only to express TCR1045, T cells engineered to express both TCR1045 and a Fas IFP preferentially persisted in the TME of tumor-bearing mice due to improved T cell proliferation and survival. Moreover, adoptive immunotherapy with IFP+ T cells significantly prolonged survival in tumor-bearing mice, relative to TCR1045 T cells lacking the IFP. Conclusions: Fas/FasL signaling can mediate T cell death in the ovarian cancer microenvironment, as well as induce activation-induced cell death, an apoptotic mechanism responsible for regulating T cell expansion. Upregulation of FasL by tumor cells and tumor vasculature represents a mechanism for protecting growing tumors from attack by tumor-infiltrating lymphocytes. As many solid tumors overexpress FasL, an IFP that converts the Fas-mediated death signal into pro-survival and proliferative signals may provide an opportunity to enhance engineered adoptive T cell therapy against many malignancies.

scholarly journals Human Papillomavirus Type 16 E7 Peptide-Directed CD8+ T Cells from Patients with Cervical Cancer Are Cross-Reactive with the Coronavirus NS2 Protein

2003 ◽  
Vol 77 (9) ◽  
pp. 5464-5474 ◽  
Author(s):  
Katja Nilges ◽  
Hanni Höhn ◽  
Henryk Pilch ◽  
Claudia Neukirch ◽  
Kirsten Freitag ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Immune Response ◽  
T Cells ◽  
Human Papillomavirus ◽  
T Cell ◽  
T Cell Responses ◽  
Cross Reactivity ◽  
Antiviral Immune Response ◽  
Human Papillomavirus Type 16 ◽  
Cell Responses

ABSTRACT Human papillomavirus type 16 (HPV16) E6 and E7 oncoproteins are required for cellular transformation and represent candidate targets for HPV-specific and major histocompatibility complex class I-restricted CD8+-T-cell responses in patients with cervical cancer. Recent evidence suggests that cross-reactivity represents the inherent nature of the T-cell repertoire. We identified HLA-A2 binding HPV16 E7 variant peptides from human, bacterial, or viral origin which are able to drive CD8+-T-cell responses directed against wild-type HPV16 E7 amino acid 11 to 19/20 (E711-19/20) epitope YMLDLQPET(T) in vitro. CD8+ T cells reacting to the HLA-A2-presented peptide from HPV16 E711-19(20) recognized also the HLA-A2 binding peptide TMLDIQPED (amino acids 52 to 60) from the human coronavirus OC43 NS2 gene product. Establishment of coronavirus NS2-specific, HLA-A2-restricted CD8+-T-cell clones and ex vivo analysis of HPV16 E7 specific T cells obtained by HLA-A2 tetramer-guided sorting from PBL or tumor-infiltrating lymphocytes obtained from patients with cervical cancer showed that cross-reactivity with HPV16 E711-19(20) and coronavirus NS252-60 represents a common feature of this antiviral immune response defined by cytokine production. Zero of 10 patients with carcinoma in situ neoplasia and 3 of 18 patients with cervical cancer showed ≥0.1% HPV16 E7-reactive T cells in CD8+ peripheral blood lymphocytes. In vivo priming with HPV16 was confirmed in patients with cervical cancer or preinvasive HPV16-positive lesions using HLA-A2 tetramer complexes loaded with the E6-derived epitope KLPQLCTEL. In contrast, we could not detect E6-reactive T cells in healthy individuals. These data imply that the measurement of the HPV16 E711-19(20) CD8+-T-cell response may reflect cross-reactivity with a common pathogen and that variant peptides may be employed to drive an effective cellular immune response against HPV.

scholarly journals Arming T Cells with a gp100-Specific TCR and a CSPG4-Specific CAR Using Combined DNA- and RNA-Based Receptor Transfer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 696 ◽  
Author(s):  
Bianca Simon ◽  
Dennis C. Harrer ◽  
Beatrice Schuler-Thurner ◽  
Gerold Schuler ◽  
Ugur Uslu
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Immune Escape ◽  
Cell Receptor ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy ◽  
Dna And Rna ◽  
Antigen Loss ◽  
Antigen Presenting

Tumor cells can develop immune escape mechanisms to bypass T cell recognition, e.g., antigen loss or downregulation of the antigen presenting machinery, which represents a major challenge in adoptive T cell therapy. To counteract these mechanisms, we transferred not only one, but two receptors into the same T cell to generate T cells expressing two additional receptors (TETARs). We generated these TETARs by lentiviral transduction of a gp100-specific T cell receptor (TCR) and subsequent electroporation of mRNA encoding a second-generation CSPG4-specific chimeric antigen receptor (CAR). Following pilot experiments to optimize the combined DNA- and RNA-based receptor transfer, the functionality of TETARs was compared to T cells either transfected with the TCR only or the CAR only. After transfection, TETARs clearly expressed both introduced receptors on their cell surface. When stimulated with tumor cells expressing either one of the antigens or both, TETARs were able to secrete cytokines and showed cytotoxicity. The confirmation that two antigen-specific receptors can be functionally combined using two different methods to introduce each receptor into the same T cell opens new possibilities and opportunities in cancer immunotherapy. For further evaluation, the use of these TETARs in appropriate animal models will be the next step towards a potential clinical use in cancer patients.

An Update on Adoptive T-Cell Therapy and Neoantigen Vaccines

2019 ◽  
pp. e70-e78 ◽  
Author(s):  
Patrick A. Ott ◽  
Gianpietro Dotti ◽  
Cassian Yee ◽  
Stephanie L. Goff
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Adoptive Cell Therapy ◽  
Adoptive T Cell Therapy ◽  
Clinical Activity ◽  
Single Chain ◽  
T Cell Therapy ◽  
Substantial Impact ◽  
Mhc Molecules

Adoptive T-cell therapy using tumor-infiltrating lymphocytes (TILs) has demonstrated long-lasting antitumor activity in select patients with advanced melanoma. Cancer vaccines have been used for many decades and have shown some promise but overall relatively modest clinical activity across cancers. Technological advances in genome sequencing capabilities and T-cell engineering have had substantial impact on both adoptive cell therapy and the cancer vaccine field. The ability to identify neoantigens—a class of tumor antigens that is truly tumor specific and encoded by tumor mutations through rapid and relatively inexpensive next-generation sequencing—has already demonstrated the critical importance of these antigens as targets of antitumor-specific T-cell responses in the context of immune checkpoint blockade and other immunotherapies. Therapeutically targeting these antigens with either adoptive T-cell therapy or vaccine approaches has demonstrated early promise in the clinic in patients with advanced solid tumors. Chimeric antigen receptor (CAR) T cells, which are engineered by fusing an antigen-specific, single-chain antibody (scFv) with signaling molecules of the T-cell receptor (TCR)/CD3 complex creating an antibody-like structure on T cells that recognizes antigens independently of major histocompatibility complex (MHC) molecules, have demonstrated remarkable clinical activity in patients with advanced B-cell malignancies, leading to several approvals by the U.S. Food and Drug Administration (FDA).

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