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Immunotherapy has transformed the treatment landscape of many cancers, with durable responses in disease previously associated with a poor prognosis. Patient selection remains a challenge, with predictive biomarkers an urgent unmet clinical need. Current predictive biomarkers, including programmed death-ligand 1 (PD-L1) (measured with immunohistochemistry), are imperfect. Promising biomarkers, including tumor mutation burden and tumor infiltrating lymphocyte density, fail to consistently predict response and have yet to translate to routine clinical practice. Heterogeneity of immune response within and between lesions presents a further challenge where fluorine 18 fluorodeoxyglucose PET/CT has a potential role in assessing response, stratifying treatment, and detecting and monitoring immune-related toxicities. Novel radiopharmaceuticals also present a unique opportunity to define the immune tumor microenvironment to better predict which patients may respond to therapy, for example by means of in vivo whole-body PD-L1 and CD8+ T cell expression imaging. In addition, longitudinal molecular imaging may help further define dynamic changes, particularly in cases of immunotherapy resistance, helping to direct a more personalized therapeutic approach. This review highlights current and emerging applications of molecular imaging to stratify, predict, and monitor molecular dynamics and treatment response in areas of clinical need., (© RSNA, 2022.)

Background: The COVID-19 pandemic has been highly disruptive for cancer care. Here, we examined the effect COVID-19 had on performance of the 62-day Cancer Waiting Time (CWT) target set by the National Health Service (NHS) in England., Methods: Data were retrospectively obtained on COVID-19 hospitalisations and CWT for NHS hospitals in England (n = 121). We produced a 'COVID-19 burden' to describe the proportion of each provider's beds occupied with COVID-19 patients. COVID-19 burden was examined against CWT performance for 1st April - 30th May 2020 (Wave 1), and 1st October - 30th November 2020 (Wave 2). Two-tailed Spearman correlations were used to identify relationships between COVID-19 burden and CWT performance amongst different referral (i.e., 2-week-wait (2 W W) and internal specialist) and tumour types. Significantly correlated variables were further examined using linear regression models., Results: COVID-19 burden was negatively associated with the percentage of 2 W W pathway referrals that met the CWT target in Wave 1 (r= -0.30, p = 0.001) and Wave 2 (r= -0.21, p = 0.02). These associations were supported by the results from our linear regression models (B for wave 1: -0.71; 95 %CI: -1.03 to -0.40; B for wave 2: -0.38; 95 %CI: -0.68 to -0.07). No associations were found between COVID-19 burden and internal specialist referrals or tumour type., Conclusion: Increased COVID-19 burden was associated with lower compliance with CWT targets amongst urgent referrals from primary care in England. This will likely be an ongoing issue due to the backlog of patients awaiting investigations and treatment., Policy Summary: As the number of cancer referrals improve, we highlight the need for changes to primary and secondary care to manage the backlog within cancer diagnostic services to alleviate the impact of COVID-19., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Using an updated dataset with more patients and extended follow-up, we further established cancer patient characteristics associated with COVID-19 death., Methods: Data on all cancer patients with a positive reverse transcription-polymerase chain reaction swab for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) at Guy's Cancer Centre and King's College Hospital between 29 February and 31 July 2020 was used. Cox proportional hazards regression was performed to identify which factors were associated with COVID-19 mortality., Results: Three hundred and six SARS-CoV-2-positive cancer patients were included. Seventy-one had mild/moderate and 29% had severe COVID-19. Seventy-two patients died of COVID-19 (24%), of whom 35 died <7 days. Male sex [hazard ratio (HR): 1.97 (95% confidence interval (CI): 1.15-3.38)], Asian ethnicity [3.42 (1. 59-7.35)], haematological cancer [2.03 (1.16-3.56)] and a cancer diagnosis for >2-5 years [2.81 (1.41-5.59)] or ≥5 years were associated with an increased mortality. Age >60 years and raised C-reactive protein (CRP) were also associated with COVID-19 death. Haematological cancer, a longer-established cancer diagnosis, dyspnoea at diagnosis and raised CRP were indicative of early COVID-19-related death in cancer patients (<7 days from diagnosis)., Conclusions: Findings further substantiate evidence for increased risk of COVID-19 mortality for male and Asian cancer patients, and those with haematological malignancies or a cancer diagnosis >2 years. These factors should be accounted for when making clinical decisions for cancer patients., (© 2021. The Author(s).)

Background: The efficacy and safety profiles of vaccines against SARS-CoV-2 in patients with cancer is unknown. We aimed to assess the safety and immunogenicity of the BNT162b2 (Pfizer-BioNTech) vaccine in patients with cancer., Methods: For this prospective observational study, we recruited patients with cancer and healthy controls (mostly health-care workers) from three London hospitals between Dec 8, 2020, and Feb 18, 2021. Participants who were vaccinated between Dec 8 and Dec 29, 2020, received two 30 μg doses of BNT162b2 administered intramuscularly 21 days apart; patients vaccinated after this date received only one 30 μg dose with a planned follow-up boost at 12 weeks. Blood samples were taken before vaccination and at 3 weeks and 5 weeks after the first vaccination. Where possible, serial nasopharyngeal real-time RT-PCR (rRT-PCR) swab tests were done every 10 days or in cases of symptomatic COVID-19. The coprimary endpoints were seroconversion to SARS-CoV-2 spike (S) protein in patients with cancer following the first vaccination with the BNT162b2 vaccine and the effect of vaccine boosting after 21 days on seroconversion. All participants with available data were included in the safety and immunogenicity analyses. Ongoing follow-up is underway for further blood sampling after the delayed (12-week) vaccine boost. This study is registered with the NHS Health Research Authority and Health and Care Research Wales (REC ID 20/HRA/2031)., Findings: 151 patients with cancer (95 patients with solid cancer and 56 patients with haematological cancer) and 54 healthy controls were enrolled. For this interim data analysis of the safety and immunogenicity of vaccinated patients with cancer, samples and data obtained up to March 19, 2021, were analysed. After exclusion of 17 patients who had been exposed to SARS-CoV-2 (detected by either antibody seroconversion or a positive rRT-PCR COVID-19 swab test) from the immunogenicity analysis, the proportion of positive anti-S IgG titres at approximately 21 days following a single vaccine inoculum across the three cohorts were 32 (94%; 95% CI 81-98) of 34 healthy controls; 21 (38%; 26-51) of 56 patients with solid cancer, and eight (18%; 10-32) of 44 patients with haematological cancer. 16 healthy controls, 25 patients with solid cancer, and six patients with haematological cancer received a second dose on day 21. Of the patients with available blood samples 2 weeks following a 21-day vaccine boost, and excluding 17 participants with evidence of previous natural SARS-CoV-2 exposure, 18 (95%; 95% CI 75-99) of 19 patients with solid cancer, 12 (100%; 76-100) of 12 healthy controls, and three (60%; 23-88) of five patients with haematological cancers were seropositive, compared with ten (30%; 17-47) of 33, 18 (86%; 65-95) of 21, and four (11%; 4-25) of 36, respectively, who did not receive a boost. The vaccine was well tolerated; no toxicities were reported in 75 (54%) of 140 patients with cancer following the first dose of BNT162b2, and in 22 (71%) of 31 patients with cancer following the second dose. Similarly, no toxicities were reported in 15 (38%) of 40 healthy controls after the first dose and in five (31%) of 16 after the second dose. Injection-site pain within 7 days following the first dose was the most commonly reported local reaction (23 [35%] of 65 patients with cancer; 12 [48%] of 25 healthy controls). No vaccine-related deaths were reported., Interpretation: In patients with cancer, one dose of the BNT162b2 vaccine yields poor efficacy. Immunogenicity increased significantly in patients with solid cancer within 2 weeks of a vaccine boost at day 21 after the first dose. These data support prioritisation of patients with cancer for an early (day 21) second dose of the BNT162b2 vaccine., Funding: King's College London, Cancer Research UK, Wellcome Trust, Rosetrees Trust, and Francis Crick Institute., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Given the immune system's importance for cancer surveillance and treatment, we have investigated how it may be affected by SARS-CoV-2 infection of cancer patients. Across some heterogeneity in tumor type, stage, and treatment, virus-exposed solid cancer patients display a dominant impact of SARS-CoV-2, apparent from the resemblance of their immune signatures to those for COVID-19 + non-cancer patients. This is not the case for hematological malignancies, with virus-exposed patients collectively displaying heterogeneous humoral responses, an exhausted T cell phenotype and a high prevalence of prolonged virus shedding. Furthermore, while recovered solid cancer patients' immunophenotypes resemble those of non-virus-exposed cancer patients, recovered hematological cancer patients display distinct, lingering immunological legacies. Thus, while solid cancer patients, including those with advanced disease, seem no more at risk of SARS-CoV-2-associated immune dysregulation than the general population, hematological cancer patients show complex immunological consequences of SARS-CoV-2 exposure that might usefully inform their care., Competing Interests: Declaration of interests The authors declare no competing interests., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

COVID-19 has forced governments to make drastic changes to healthcare systems. To start making informed decisions about cancer care, we need to understand the scale of COVID-19 infection. Therefore, we introduced swab testing for patients visiting Guy's Cancer Centre. Our Centre is one of the largest UK Cancer Centers at the epicenter of the UK COVID-19 epidemic. The first COVID-19 positive cancer patient was reported on 29 February 2020. We analyzed data from 7-15 May 2020 for COVID-19 tests in our cancer patients. 2,647 patients attended for outpatient, chemotherapy, or radiotherapy appointments. 654 were swabbed for COVID-19 (25%). Of those tested, 9 were positive for COVID-19 (1.38%) of which 7 were asymptomatic. Cancer service providers will need to understand their local cancer population prevalence. The absolute priority is that cancer patients have the confidence to attend hospitals and be reassured that they will be treated in a COVID-19 managed environment.

Immune checkpoint inhibitors are a novel class of cancer treatment that have improved outcomes for a subset of cancer patients. They work by antagonising inhibitory immune pathways, thereby augmenting immune-mediated antitumour responses. However, immune activation is not cancer-specific and often results in the activation of immune cells in non-cancer tissues, resulting in off-target immune-mediated injury and organ dysfunction. Diarrhoea and gastrointestinal tract inflammation are common and sometimes serious side-effects of this type of therapy. Prompt recognition of gastrointestinal toxicity and, in many cases, rapid institution of anti-inflammatory or biologic therapy (or both) is required to reverse these complications. Management of organ-specific complications benefits from multidisciplinary input, including engagement with gastroenterologists for optimal management of immune checkpoint inhibitor-induced enterocolitis. In this British Society of Gastroenterology endorsed guidance document, we have developed a consensus framework for the investigation and management of immune checkpoint inhibitor-induced enterocolitis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Cancer immune therapy with checkpoint inhibitors (CPIs) has changed the landscape of treatment for a growing number of indications. These drugs are associated with a specific mechanism of action that has profound implications for both immunology and inflammatory disease. This article looks to set the scene covering the history of CPI therapy to date and outlining the likely future developments., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Antibody Fc-driven engagement of macrophages is critical for evoking cellular activation and effector functions and influencing tumour-associated macrophage (TAM) recruitment. We previously reported that IgE class antibodies promote restriction of cancer growth in rodent models associated with significant TAM infiltration. However, the human macrophage-associated IgE-Fc Receptor (FcεR) axis remains unexplored. We investigated the effects of anti-tumour IgE stimulation on human macrophage activation., Methods: Human blood monocyte-differentiated quiescent (M0), classically-(M1) and alternatively-(M2) activated macrophages were crosslinked with IgE and polyclonal antibodies to mimic immune complex formation. We examined surface marker expression, cytokine secretion, protein kinase phosphorylation and gene expression in IgE-stimulated macrophages and IgE antibody-dependent macrophage-mediated cytotoxicity (ADCC) against tumour cells., Findings: A proportion (40%) of M2 and (<20%) M0 and M1 macrophages expressed the high-affinity IgE receptor FcεRI. IgE crosslinking triggered upregulation of co-stimulatory CD80, increased TNFα, IFNγ, IL-1β, IL-12, IL-10, IL-13, CXCL9, CXCL11 and RANTES secretion by M0 and M2 and additionally enhanced MCP-1 by M2 macrophages. IgE-stimulated M1 macrophages retained secretion of pro-inflammatory cytokines. IgE crosslinking enhanced the FcεRI-dependent signalling pathway, including phosphorylation of the Lyn kinase, ERK1/2 and p38 in M2 macrophages and upregulated Lyn gene expression by M1 and M2 macrophages. Anti-tumour IgE engendered ADCC of cancer cells by all macrophage subsets., Interpretation: IgE can engage and re-educate alternatively-activated macrophages towards pro-inflammatory phenotypes and prime all subsets to mediate anti-tumour functions. This points to IgE-mediated cascades with potential to activate immune stroma and may be significant in the clinical development of strategies targeting tumour-resident macrophages., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Immune checkpoint inhibitor therapies are a novel group of monoclonal antibodies with proven effectiveness in a wide range of malignancies, including melanoma, renal cell carcinoma, non-small-cell lung cancer, urothelial carcinoma and Hodgkin lymphoma. Their use in a range of other indications, such as gastrointestinal and head and neck cancer, is currently under investigation. The number of agents included in this drug group is increasing, as is their use. Although they have the potential to improve the treatment of advanced malignancies, they are also associated with a substantial risk of immune-related adverse events. The incidence of gastrointestinal toxicity associated with their use is second only in frequency to dermatological toxicity. Thus, gastroenterologists can expect to be increasingly frequently consulted by oncologists as part of a multidisciplinary approach to managing toxicity. Here, we describe this novel group of agents and their mechanisms of action. We review the manifestations of gastrointestinal toxicity associated with their use so that it can be recognized early and diagnosed accurately. We also discuss the proposed mechanisms underlying this toxicity and describe an algorithmic and, wherever possible, evidence-based approach to its management.

Adoptive cell therapy using gene-modified T-cells has achieved impressive results in the treatment of B-cell malignancies. However, the development of similar strategies to treat solid tumors raises challenges with respect to tumor antigen selection and the achievement of efficient T-cell homing, survival and sustained effector function within the tumor microenvironment. To address these challenges, we have developed a gene-modified cellular therapy called T4 immunotherapy. To generate T4 immunotherapy, autologous T-cells are engineered by retroviral transduction to co-express two transgenes: (1) a chimeric antigen receptor (CAR), T1E28z, targeted against a range of ErbB homodimers and heterodimers and (2) a chimeric cytokine receptor, 4αβ, that allows the selective ex vivo expansion of engineered cells using interleukin-4. Targeting of the extended ErbB network using CAR T-cells is supported by prevalence of ErbB dysregulation in diverse solid tumors and the clinical impact of monoclonal antibody therapy directed against members of this family. However, the key obstacle to effective clinical translation is risk of on-target toxicity owing to the lower level expression of ErbB family members in many healthy tissues. To de-risk T4 immunotherapy in man, we are undertaking a trial in patients with locally advanced or recurrent head and neck squamous cell carcinoma. In that setting, engineered T-cells are injected directly into the tumor without prior lymphodepletion, an approach that we believe will minimize risk of toxicity. This chapter outlines how we plan to advance the development of T4 immunotherapy thereafter in Phase II clinical testing. In that setting, regional (intracavitary) approaches will be used to administer this therapy to patients with epithelial ovarian cancer and malignant pleural mesothelioma.

Purpose: Little is known about the influence of socioeconomic factors on patient access to cancer trials. Differences should be considered to ensure generalizability of trial results and equality of access., Methods: Phase I trials unit referrals at our center over 5 years, from 2007 to 2012, were reviewed. Socioeconomic status was defined by the Index of Multiple Deprivation (IMD; 1, least deprived; 5, most deprived). Multivariate analysis was performed comparing incident cancer cases with referred patients and those ultimately enrolled onto a trial., Results: Four hundred thirty patients were referred (median age, 62 years). Compared with 10,784 incident cases, referral was less likely for patients in the more-deprived quintiles compared with the least deprived (IMD 5: odds ratio [OR], 0.53; 95% CI, 0.38 to 0.74). Once reviewed in the unit, enrollment onto a trial was not affected (IMD 5: OR, 0.81; 95% CI, 0.40 to 1.63). Ethnicity analysis showed the nonwhite population was less likely to be recruited (OR, 0.48; 95% CI, 0.26 to 0.88). This relationship was lost with adjustment for age, sex, cancer type, and deprivation index., Conclusion: We show for the first time to our knowledge that socioeconomic status affects early-phase cancer trial referrals. The least-deprived patients are almost twice as likely to be referred compared with the most deprived. This may be because more-deprived patients are less suitable for a trial-as a result of comorbidities, for example-or because of inequalities that could be addressed by patient or referrer education. Once reviewed at the unit, enrollment onto a trial is not affected by deprivation.