Jamie Honeychurch

The University of Manchester

Introduction: The glycoengineered type II anti-CD20 monoclonal antibody obinutuzumab has been licensed for treatment in follicular non-Hodgkin lymphoma and B-CLL following clinical trials demonstrating superior outcomes to standard of care treatment. However, ultimately many patients still relapse, highlighting the need to understand the mechanisms...

Focal radiation therapy (RT) has attracted considerable attention as a combinatorial partner for immunotherapy (IT), largely reflecting a well-defined, predictable safety profile and at least some potential for immunostimulation. However, only a few RT-IT combinations have been tested successfully in patients with cancer, highlighting the urgent ne...

Despite breakthroughs in immune checkpoint inhibitors (ICI), the majority of tumors, including those poorly infiltrated by CD8+ T cells or heavily infiltrated by immunosuppressive immune effector cells, are unlikely to result in clinically meaningful tumor responses. Radiation therapy (RT) has been combined with ICI to potentially overcome this res...

Introduction The ability to modulate and enhance the anti-tumor immune responses is critical in developing novel therapies in cancer. The Tumor Necrosis Factor (TNF) Receptor Super Family (TNFRSF) are potentially excellent targets for modulation which result in specific anti-tumor immune responses. CD40 is a member of the TNFRSF and several clinica...

Micronucleus (MN) formation is routinely used as a biodosimeter for radiation exposures and has historically been used as a measure of DNA damage in cells. Strongly correlating with dose, MN are also suggested to indicate radiation quality, differentiating between particle and photon irradiation. The “gold standard” for measuring MN formation is Fe...

Significance Radiotherapy is one of the most common forms of cancer treatment used today. Its impact in directly killing cancer cells, and on antitumour immunity, is well recognized, but its effect on immune cell–cancer cell interactions is not fully understood. Here, we show that irradiation of cancer cells surprisingly leads to resistance against...

Radiotherapy (RT) is a highly effective anticancer treatment that is delivered to more than half of all patients with cancer. In addition to the well-documented direct cytotoxic effects, RT can have immunomodulatory effects on the tumour and surrounding tissues. These effects are thought to underlie the so-called abscopal responses, whereby RT gene...

Simple Summary Radiotherapy is an important component of cancer treatment, given to around half of all cancer patients. Radiotherapy is known to be very effective at directly killing cancer but, until recently, the important effects that radiotherapy has on the surrounding immune cells were not widely appreciated. Over the last decade, immunotherap...

Radiotherapy (RT) is a highly effective anti-cancer therapy delivered to around 50–60% of patients. It is part of therapy for around 40% of cancer patients who are cured of their disease. Until recently, the focus of this anti-tumour efficacy has been on the direct tumour cytotoxicity and RT-induced DNA damage. Recently, the immunomodulatory effect...

Simple Summary Pre-clinical models are required to develop new therapeutics to improve patient care. In the prostate cancer field, significant progress has been made in the development of in vivo models but with a predominant focus on transgenics, which are time and cost prohibitive. Conversely, other available models do not closely resemble patien...

Immunotherapy has potential to improve outcome for cancer patients. The MRI biomarker apparent diffusion co-efficient (ADC) can map response to radiotherapy (RT) through its sensitivity to changes in tumor fluid and cellularity. The role of ADC in evaluating immunotherapy agents is unknown, despite investigators using ADC change as an exploratory e...

The premise that therapies targeting immune checkpoints may enhance radiation therapy (RT)-induced anti-tumour immunity is being rigorously explored in the pre-clinical setting, and early clinical trials testing this hypothesis are beginning to report. Whilst such approaches may prove efficacious in certain settings, it is likely that many tumor ty...

Background: Allograft models enable characterisation of genomic drivers and treatment responses by modelling immune and micro-environmental changes more accurately than xenografts. Despite this, few models are available to the prostate cancer (PCa) community. This study presents a novel allograft model of high-risk, localised PCa. In characterising...

Purpose: MRI biomarkers of tumor response to treatment are typically obtained from parameters derived from a model applied to pre-treatment and post-treatment data. However, as tumors are spatially and temporally heterogeneous, different models may be necessary in different tumor regions, and model suitability may change over time. This work evalu...

418 Background: Many patients with bladder cancer (BC) undergo radiotherapy (RT) during the course of their treatment. There is emerging evidence that RT can cause immune stimulatory changes within the tumour microenvironment (TME), potentially contributing to its efficacy. We aimed to determine if RT induces immunogenic changes in murine BC cell l...

Abstract Purpose We have previously developed the caspase-based radiotracer, 18F-ICMT-11, for PET imaging to monitor treatment response. We further validated 18F-ICMT-11 specificity in a murine melanoma death-switch tumour model with conditional activation of caspase-3 induced by doxycycline. Methods Caspase-3/7 activity and cellular uptake of 18F-...

In addition to tumouricidal activity, radiotherapy is now recognized to display potent immunostimulatory properties that can contribute to the generation of anti-cancer immune responses. Treatment with radiation can induce a variety of pro-immunogenic and phenotypic changes in malignant cells, and recalibrate the immune contexture of the tumour mic...

An urgent need exists to improve the outcomes of patients with muscle-invasive bladder cancer (MIBC), and especially of those with metastatic disease. Treatments that enhance antitumour immune responses — such as immune-checkpoint inhibition — provide an opportunity to do this. Despite initial success, durable response rates in patients with advanc...

Purpose: Radiotherapy (RT) is a highly effective anti-cancer treatment forming part of the standard of care for the majority of patients, but local and distal disease recurrence remains a major cause of mortality. RT is known to enhance tumor immunogenicity; however, the contribution and mechanisms of RT induced immune responses are unknown. Exper...

Radiotherapy (RT) is effective at cytoreducing tumours and until relatively recently the focus in radiobiology has been on the direct effects of RT on the tumour. Increasingly, however, the effect of RT on the tumour vasculature, tumour stroma and immune system are recognized as important to the overall outcome. RT is known to lead to the induction...

Tumor cells dying after cytotoxic therapy are a potential source of antigen for T-cell priming. Antigen-presenting cells (APC) can cross-present MHC I–restricted peptides after the uptake of dying cells. Depending on the nature of the surrounding environmental signals, APCs then orchestrate a spectrum of responses ranging from immune activation to...

Tumor cells dying after cytotoxic therapy are a potential source of antigen for T-cell priming. Antigen-presenting cells (APC) can cross-present MHC I restricted peptides following uptake of dying cells. Depending on the nature of the surrounding environmental signals APC then orchestrate a spectrum of responses ranging from immune activation to in...

Strategies to augment anti-cancer immune responses have recently demonstrated therapeutic utility. To date clinical success has been achieved through targeting co-inhibitory checkpoints such as CTLA-4, PD-1, and PD-L1. However, approaches that target co-activatory pathways are also being actively being developed. Here we report that the novel TLR7-...

Introduction: After years of limited success, progress of anti-cancer immuno-therapeutics has been considerable over the past decade. Key to this progress has been the application of new biological insights around the importance and nature of immune checkpoints that are able to reverse down-regulation of anti-tumor immunity. Areas covered: An ov...

Radiotherapy is a major part in the treatment of most common cancers, but many patients experience local recurrence with metastatic disease. In evaluating response biomarkers, we found that low doses of fractionated radiotherapy led to PD-L1 upregulation on tumor cells in a variety of syngeneic mouse models of cancer. Notably, fractionated radiothe...

Radiation therapy (RT) is administered to around 50% of all cancer patients making it one of the most important cancer treatments. In addition to the direct cytoreductive effect of RT there is increasing evidence that radiation-induces immunogenic tumor cell death. Despite the immunogenicity of RT-induced tumor cell death, RT delivered to tumours i...

Introduction: The anti-CD20 mAb rituximab has revolutionized the treatment of B-cell malignancies, improving outcome for patients. Despite these improvements, the majority of patients still relapse and become refractory to rituximab. Further efforts to improve anti-CD20 mAb efficacy have recently focused on obinutuzumab /GA101, a novel anti-CD20 m...

Apoptotic cells have long been considered as intrinsically tolerogenic or unable to elicit immune responses specific for dead cell-associated antigens. However, multiple stimuli can trigger a functionally peculiar type of apoptotic demise that does not go unnoticed by the adaptive arm of the immune system, which we named “immunogenic cell death” (I...

Although topical TLR7 therapies such as imiquimod have proved successful in the treatment of dermatological malignancy, systemic delivery may be required for optimal immunotherapy of nondermatological tumors. We report that intravenous delivery of the novel small molecule TLR7 agonist, DSR-6434, leads to the induction of type 1 interferon and activ...

Understanding the immune response to the death of malignant cells is critical for the development of therapeutic strategies designed to stimulate the immune system against cancer. We have developed an inducible caspase-3-mediated death switch model to explore the effects of apoptosis on the host immune system, demonstrating that the synchronous apo...

Effective anticancer treatments often result in the induction of large amounts of tumour cell death. In vivo, such dying tumour cells are a potential source of antigens for T-cell stimulation. Although apoptosis is generally considered nonimmunogenic, recent evidence suggests that some anticancer therapies that induce apoptosis can elicit antitumou...

ABSTRACT The aim of this study was to assess the immunogenic potential of irradiated lymphoma cells in vivo and determine whether immunogenicity can be enhanced by modulation of the host immune system. Syngeneic murine lymphoma models irradiated ex vivo were used as an orthotopic cellular vaccination prior to challenge with viable tumor cells. We d...

Passive immunotherapy with monoclonal antibodies has improved outcome for patients with B cell malignancies although many still relapse and little progress has been made with T cell malignancies. Novel treatment approaches are clearly required in this disease setting. There has been much recent interest in developing therapeutic approaches to enhan...

Monoclonal antibodies (mAbs) have revolutionized the treatment of B-cell malignancies. Although Fc-dependent mechanisms of mAb-mediated tumor clearance have been extensively studied, the ability of mAbs to directly evoke programmed cell death (PCD) in the target cell and the underlying mechanisms involved remain under-investigated. We recently demo...

1651 Background Anti-CD20 monoclonal antibodies (mAbs), most notably rituximab, have revolutionized the treatment of B-cell malignancies with substantially improved clinical outcome for patients. However, a proportion of patients still relapse and become refractory to rituximab. Therefore, several next-generation mAbs are being developed to improv...

The anti-CD20 mAb rituximab has substantially improved the clinical outcome of patients with a wide range of B-cell malignancies. However, many patients relapse or fail to respond to rituximab, and thus there is intense investigation into the development of novel anti-CD20 mAbs with improved therapeutic efficacy. Although Fc-FcγR interactions appea...

3245 Whilst modern treatment approaches cure a high number of patients with acute lymphoblastic leukemia (ALL), little progress has been made in the treatment of refractory and relapsed ALL and new treatment approaches are needed. We recently demonstrated that anti-HLA-DR class II monoclonal antibody (mAb) L243 induces a novel non-apoptotic mode of...

725 The addition of the anti-CD20 monoclonal antibody (mAb) rituximab to chemotherapy has substantially improved the clinical outcome of patients with a wide range of B-cell malignancies. Despite this success, many patients are not cured by standard approaches and there is intense investigation into the development of new-generation anti-CD20 mAbs...

mAbs are becoming increasingly utilized in the treatment of lymphoid disorders. Although Fc-FcgammaR interactions are thought to account for much of their therapeutic effect, this does not explain why certain mAb specificities are more potent than others. An additional effector mechanism underlying the action of some mAbs is the direct induction of...

Radioimmunotherapy is a highly effective treatment for some hematologic malignancies; however, the underlying mechanisms of tumor clearance remain poorly understood. We have previously shown that both targeted radiation using (131)I-labeled anti-MHC class II (MHCII) monoclonal antibody (mAb) plus mAb signaling with unlabeled anti-idiotype are requi...

Treatment of B-cell lymphoma with combined radiation and anti-CD40 monoclonal antibody (mAb) can result in long-term CD8+ T-cell mediated tumor protection. Survival correlates closely with radiation dose, such that for combinations of 5 Gy and anti-CD40 mAb over 80% of animals survive beyond 100 days, but at 2 Gy maximum survival time is only a wee...

The HIV-1 Nef protein plays a critical role in viral pathogenesis. Nef has been shown to modulate dendritic cell (DC) function, in particular perturbing their ability to present Ag. To further characterize the effects of Nef on DCs, we established a panel of transfectants of the murine DC line, DC2.4, stably expressing differing levels of either wi...

Monoclonal antibody (mAb)-based immunotherapy is now established as an important option for treating some cancers. The antitumor effects may be further enhanced by combining mAb with conventional chemotherapy. Certain novel immunomodulatory mAbs such as anti-CD40 have shown significant activity in preclinical models. We therefore assessed the effic...

Immunotherapy with mAb is emerging as an important component of treatment for B-cell lymphoma. Furthermore, anti-tumor effects may be enhanced by combining mAb with a range of conventional cancer treatments and recently impressive results have been acheived with mAb in combination with chemotherapy. Here, we have assessed the efficacy of combining...

Radioimmunotherapy (RIT) has emerged as an effective treatment for lymphoma, however the underlying mechanisms are poorly understood. We therefore investigated the relative contributions of antibody and targeted radiation to the clearance of tumor in vivo, using 2 different syngeneic murine B-cell lymphoma models. Although RIT with (131)I-anti-majo...

The mechanisms of interaction between anti-CD40 monoclonal antibody (mAb) therapy and external beam irradiation were investigated in 2 syngeneic B-cell lymphoma models. We have established doses of anti-CD40 mAb and irradiation which, although ineffective when given singly, were capable of providing long-term protection when used in combination. Fu...

A flow cytometric (FCM) assay has been developed for the determination of cell-mediated cytotoxicity (CMC). In the assay, the target tumour cell population was labelled with a membrane dye, PKH-26, prior to incubation with splenocyte effector cells. Cell death within the target population was assessed by the addition of the viability probe TO-PRO-3...

We report the in vivo radioimmunotherapy (RIT) of a new variant of the BCL1 syngeneic mouse B-cell lymphoma model, pi-BCL1, using a panel of monoclonal antibodies (MoAb) reactive with B cell-associated antigens (CD19, CD22, CD40, MHC II, and idiotype). MoAb were radiolabeled with 131I or used in conjunction with external beam irradiation. When admi...

CD64 (FcgammaRI) receptors represent highly potent trigger molecules for activated polymorphonuclear cells (PMN) and mediate lysis of a range of tumors in the presence of appropriate monoclonal antibodies. An huCD64 transgenic mouse model designed to analyze the therapeutic activity of a panel of bispecific F(ab')(2) (BsAb) in retargeting granulocy...

We report a new variant of the BCL1 syngeneic mouse B-cell lymphoma model which we have called pi -BCL1. pi -BCL1 can be established as a syngeneic tumor in BALB/c mice. Tumors can be removed, prepared and easily grown in liquid culture and subsequently transferred back successfully as syngeneic rumors. As a syngeneic tumor pi -BCL1 behaves more li...

CD64 (Fc?RI) receptors represent highly potent trigger molecules for activated polymorphonuclear cells (PMN) and mediate lysis of a range of tumors in the presence of appropriate monoclonal antibodies. An huCD64 transgenic mouse model designed to analyze the therapeutic activity of a panel of bispecific F(ab')2(BsAb) in retargeting granulocyte–colo...

CD64 (FcγRI) receptors represent highly potent trigger molecules for activated polymorphonuclear cells (PMN) and mediate lysis of a range of tumors in the presence of appropriate monoclonal antibodies. An huCD64 transgenic mouse model designed to analyze the therapeutic activity of a panel of bispecific F(ab')2(BsAb) in retargeting granulocyte–colo...

Monoclonal antibodies (mAbs) appear to offer many benefits for the treatment of cancer and in particular lymphoma (1). They are natural products that can be made with precise specificity and in almost unlimited amounts. In addition, mAbs can be selected or engineered to efficiently recruit the body's effector systems, such as complement and natural...

p>The incidence of lymphoma is rising, now representing 3% of cancers in the UK alone. Current treatments include chemotherapy and radiotherapy, but whilst significant remission is often observed, responses frequently prove not to be durable. Thus, alternative treatments are sought. One such alternative is the use of bispecific antibodies (BsAb),...

Despite the recent success of mAb in the treatment of certain malignancies, there is still considerable uncertainty about the mechanism of action of anti-cancer Abs. Here, a panel of rat anti-mouse B cell mAb, including Ab directed at surface IgM Id, CD19, CD22, CD40, CD74, and MHC class II, has been investigated in the treatment of two syngeneic m...

Despite the success of mAb and bispecific (bs)Ab in the treatment of certain malignancies, there is still considerable uncertainty about the most appropriate format in which they should be used. In the current work we have investigated a panel of bsAb [IgG and F(ab)2] with dual specificity for T cells and neoplastic B cells. Throughout this work, a...

Thesis (Ph. D.)--University of Southampton, 2000.