scholarly journals Enabling T Cell Recruitment to Tumours as a Strategy for Improving Adoptive T Cell Therapy

2017 ◽  
Vol 13 (01) ◽  
pp. 66 ◽  
Author(s):  
Bruno Cadilha ◽  
Klara Dorman ◽  
Felicitas Rataj ◽  
Stefan Endres ◽  
Sebastian Kobold ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Therapeutic Potential ◽  
Cell Activity ◽  
Cell Lineage ◽  
Solid Tumours ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy

Immunotherapy has successfully been implemented as the standard of care in a number of oncologic indications. A hallmark of cancer immunotherapy is the successful activation of T cells against cancer cells, leading to unparalleled efficacy for some tumour entities. However, current approved approaches are not specific, limiting both their activity and their safety. A more tailored way of using the therapeutic potential of T cells is adoptive T cell therapy, which encompasses ex vivo T cell manipulation and reinfusion to patients suffering from cancer. In haematologic malignancies such as acute lymphatic leukaemia of the B cell lineage, T cells modified with a chimeric antigen receptor against the B cell lineage antigen CD19 induce remissions in a high proportion of patients. In contrast, patients suffering from advanced solid tumours have shown little benefit from cell-based approaches. This is partly due to limited access of T cells to the tumour tissue, consequently restricting T cell activity. In this review, we focus on the limitations of T cell trafficking towards solid tumours. We summarise the existing knowledge on lymphocyte migration to understand how this pathway may be used to open therapeutic approaches for a broader range of indications. We also review new strategies targeting the tumour site that aid naturally occurring or gene-engineered T cells to migrate to solid tumours. Finally, we discuss how guiding T cells towards the tumour might contribute in harnessing their full cytolytic potential.

Tumor Specific T Cells Modified to Secrete IL-12 Eradicate Systemic Tumors in the Absence of Prior Toxic Chemotherapy Conditioning Regimens

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3120-3120
Author(s):  
Hollie J. Pegram ◽  
James Lee ◽  
Erik Hayman ◽  
Gavin H Imperato ◽  
Thomas J. Tedder ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Cell Activity ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy ◽  
Tumor Bearing ◽  
Conditioning Regimens ◽  
Ifn Γ

Abstract Abstract 3120 T cells may be genetically modified to target tumor-associated antigens through the retroviral transduction of genes encoding chimeric antigen receptors (CARs). We have previously generated a series of CARs specific to the CD19 antigen expressed on most B cell tumors. In xenotransplant models of disease we have shown that human T cells expressing CD19 targeted CARs successfully eradicate established B cell tumors in immune compromised SCID-Beige mice. To further our understanding of the in vivo biology of CAR modified T cells, we generated a more clinically relevant syngeneic, immune competent tumor model utilizing CD19 knock out (mCD19−/−) human CD19 knock in (hCD19+/−) C57BL6 transgenic mice (C57BL6(mCD19−/− hCD19+/−)) bearing systemic syngeneic EL4(hCD19+) thymoma tumors. Treatment of tumor bearing mice with syngeneic T cells modified to express the CD19 targeted 19m ζ CAR alone failed to either eradicate tumor or induce predicted B cell aplasias. However, prior lymphodepletion with cyclophosphamide followed by infusion of 19m ζ+ T cells successfully eradicated tumor in 83% of treated mice and induced long term B cell aplasias. Translation of this therapy to the clinic has also revealed that optimal responses require pre-conditioning regimens. Given the toxicity of pre-conditioning treatments, these therapies are largely restricted to younger, healthier patients able to tolerate such intensive regimens. To further understand the mechanisms of action of improved therapy following prior cyclophosphamide therapy, we demonstrated markedly enhanced serum levels of the IL-12 and IFN γ cytokines as well as a marked reduction of endogenous CD4+ regulatory T cells. We postulated that IL-12, which induces IFN γ secretion, may in part explain the enhanced anti-tumor efficacy following prior lymphodepletion, and may potentially obviate the need for toxic conditioning pre-treatments. To address this hypothesis, we modified CAR+ T cells to constitutively secrete IL-12. Subsequent adoptive therapy of EL4(hCD19+) tumor bearing C57BL6(mCD19−/− hCD19+/−) mice with hCD19 targeted IL-12 secreting T cells successfully eradicated disease in 75% of treated mice and induced predicted B cell aplasias in the absence of prior lymphodepletion. Significantly, we found that this enhanced hCD19 targeted T cell activity required the infusion of both CD4+ and CD8+ gene modified T cells, and was further dependent upon autocrine IL-12 stimulation of the modified tumor targeted T cells as well as modified T cell IFN γ secretion and stimulation. To our knowledge, this is the first time adoptive T cell transfer has been demonstrated to successfully eradicate tumor in the absence of prior conditioning regimens. Therefore, these data support the rapid translation of this adoptive T cell therapy to the clinic, as it may enhance the anti-tumor efficacy of this therapy and further expand the patient population eligible for adoptive T cells therapy. Disclosures: No relevant conflicts of interest to declare.

Impact of the Conditioning Chemotherapy On Outcomes in Adoptive T Cell Therapy: Results From a Phase I Clinical Trial of Autologous CD19-Targeted T Cells for Patients with Relapsed CLL

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1797-1797 ◽  
Author(s):  
Jae H. Park ◽  
Isabelle Rivière ◽  
Xiuyan Wang ◽  
Jolanta Stefanski ◽  
Qing He ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Phase I ◽  
B Cell ◽  
Tumor Burden ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy ◽  
Conditioning Therapy

Abstract Abstract 1797 Patient T cells may be genetically modified to express chimeric antigen receptors (CARs) targeted to antigens expressed on tumor cells. We have previously reported initial results from a phase I clinical trial treating patients with chemotherapy refractory chronic lymphocytic leukemia (CLL) with autologous T cells modified to express the 19–28z CAR targeted to the CD19 antigen expressed on most B cell malignancies (Brentjens RJ, Rivière I et al., Blood, 2011;118(18):4817-28). In the previous reported cohorts of 8 patients, CAR-modified T cells were infused in the setting of rapidly progressive and chemotherapy refractory disease. Although prior conditioning therapy with cyclophosphamide enhanced in vivo persistence of the modified T cells, all patients had cyclophosphamide-resistant disease and none experienced objective remissions or significant hematologic recovery. We hypothesized that suboptimal clinical response observed in the study was because of a large tumor burden at the time of T cell infusion and refractoriness to conditioning therapy. On the basis of these findings, we have modified the protocol to allow prior cytoreductive therapy and conditioning with chemotherapeutic agents based on predicted chemosensitivity. Since these protocol modifications, two patients have been treated. Both had relapsed disease with unfavorable disease phenotype following previous treatments with various chemotherapy and biologic regimens. Of the two patients treated to date, one achieved partial remission (PR) and the other attained minimal residual disease (MRD)-negative complete remission (CR) according to standard international criteria. The first patient experienced reduction in peripheral lymphocytosis and obtained stable disease with persistent anemia and thrombocytopenia after two cycles of bendamustine and rituximab (BR). Following the bendamustine conditioning and modified T cell infusion, PR was achieved with complete hematologic recovery, lasting for more than 8 months at the time of this report. The second patient achieved PR following two cycles of BR and subsequently attained MRD-negative CR with concomitant development of B cell aplasia after receiving the bendamustine conditioning and CAR-modified T cells. At the time of this report, the response has been sustained for more than 5 months. Notably, this patient has long-term persistence of the CAR-modified T cells, detected at 12 weeks following the T cell infusion. No significant toxicities were observed in the two patients, except for fevers lasting 3–4 days and transient grade 2 hypoxia. While the number of treated patients on the revised protocol is too small to draw a definitive conclusion, our findings of a significant improvement in the degree and depth of response with the bendamustine conditioning compared to our previous cohorts of cyclophosphamide-refractory CLL who received cyclophosphamide as their conditioning suggest a potentially greater effect of conditioning regimens through tumor burden reduction than the induction of a supportive cytokine response or lymphocyte depletion. In light of these initial observations, the role of the conditioning chemotherapy regimen given prior to adoptive T cell therapy needs to be carefully evaluated since not all regimens may ultimately be equally effective with respect to clinical outcomes. Disclosures: Lamanna: Celgene: Membership on an entity's Board of Directors or advisory committees, 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 B-cell Maturation Antigen Is a Promising Target for Adoptive T-cell Therapy of Multiple Myeloma

2013 ◽  
Vol 19 (8) ◽  
pp. 2048-2060 ◽  
Author(s):  
Robert O. Carpenter ◽  
Moses O. Evbuomwan ◽  
Stefania Pittaluga ◽  
Jeremy J. Rose ◽  
Mark Raffeld ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Adoptive T Cell Therapy ◽  
Cell Maturation ◽  
T Cell Therapy ◽  
B Cell Maturation ◽  
Promising Target ◽  
B Cell Maturation Antigen

scholarly journals Human CD4+ T cells specific for dominant epitopes of SARS-CoV-2 Spike and Nucleocapsid proteins with therapeutic potential

2021 ◽  
Author(s):  
Johan Verhagen ◽  
Edith Van der Meijden ◽  
Vanessa Lang ◽  
Andreas Kremer ◽  
Simon Völkl ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Cd4 T Cells ◽  
Cellular Therapy ◽  
Therapeutic Potential ◽  
Cell Receptor ◽  
Haematopoietic Stem Cell ◽  
T Cell Therapy ◽  
Immunological Protection

Since December 2019, Coronavirus disease-19 (COVID-19) has spread rapidly across the world, leading to a global effort to develop vaccines and treatments. Despite extensive progress, there remains a need for treatments to bolster the immune responses in infected immunocompromised individuals, such as cancer patients who recently underwent a haematopoietic stem cell transplantation. Immunological protection against COVID-19 is mediated by both short-lived neutralising antibodies and long-lasting virus-reactive T cells. Therefore, we propose that T cell therapy may augment efficacy of current treatments. For the greatest efficacy with minimal adverse effects, it is important that any cellular therapy is designed to be as specific and directed as possible. Here, we identify T cells from COVID-19 patients with a potentially protective response to two major antigens of the SARS-CoV-2 virus, Spike and Nucleocapsid protein. By generating clones of highly virus-reactive CD4+ T cells, we were able to confirm a set of 9 immunodominant epitopes and characterise T cell responses against these. Accordingly, the sensitivity of T cell clones for their specific epitope, as well as the extent and focus of their cytokine response was examined. Moreover, by using an advanced T cell receptor (TCR) sequencing approach, we determined the paired TCR sequences of clones of interest. While these data on a limited population require further expansion for universal application, the results presented here form a crucial first step towards TCR-transgenic CD4+ T cell therapy of COVID-19.

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.

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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