The Christie School of Oncology: Christie Research Publications Repository
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Solid tumour cellular therapy - principles of toxicity management
No full textFollowing the Food and Drug Administration (FDA) approval of lifileucel and afami-cel for patients with advanced melanoma and synovial sarcoma, respectively, there is a need for improved understanding and guidance regarding the management of toxicity associated with adoptive cellular therapies (ACTs) for solid tumours. Further approvals are expected in coming years, with toxicity management representing a significant consideration for centres looking to implement such advanced therapy medicinal products. Importantly, first-generation tumour-infiltrating lymphocyte therapies are associated with unique toxicities compared with gene-modified T-cell therapies such as chimeric antigen receptor T-cell therapy (CAR T) and T-cell receptor-modified therapy (TCR T), presenting novel challenges for treating healthcare professionals. Extrapolating from experience with CAR T in the field of haemato-oncology, coupled with the historical use of high-dose interleukin-2 in solid tumour therapeutic regimens and more recently lifileucel and afami-cel, has led to the development of core principles for managing toxicity, which is discussed here. Looking to the future, a rapidly developing field with next-generation ACT products, a basic knowledge of such core principles will be an important foundation for healthcare professionals working in this space
Radiation-induced extracellular matrix remodelling drives prognosis and predicts radiotherapy response in muscle-invasive bladder cancer
No full textMuscle-invasive bladder cancer (MIBC) is a prevalent disease that can be treated with radiotherapy, but has a poor prognosis. Radiation-induced extracellular matrix (ECM) remodelling and fibrosis can induce tumour resistance and recurrence, but have not been studied in MIBC. Here, we aimed to characterise the impact of radiation on the ECM composition of MIBC. Three MIBC cell lines (T24, UMUC3, J82) were treated with fractionated radiation. We used proteomics to analyse the ECM composition produced by surviving cancer cells and immunofluorescence to investigate changes in the morphology and number of ECM fibres. We evaluated the RNA expression of identified ECM proteins (FN1, COL5A1, COL1A1, TNF6AIP6, FLG) in one cystectomy (TCGA-BLCA, n=397) and two radiotherapy (BC2001, n=313; BCON, n=151) cohorts. There were 613 proteins affected by radiation (p(adj)2 or <-2), 68 of which were ECM-associated proteins. There was a general increase in proteases and protease regulators but heterogeneity across cell lines. Enrichment analysis showed ECM organisation was the primary pathway affected. Immunofluorescence confirmed radiation affected ECM structure, generally, reducing the number, length and width of fibres. Five ECM genes of interest were identified (COL1A1, COL5A2, FN1, FLG, TNFAIP6), constituting an ECM signature. High FN1, COL1A1, TNF6AIP6 mRNA levels and ECM signature scores were independent poor prognostic markers, while FLG mRNA expression independently predicted radiotherapy benefit in a meta-analysis (n=861). We found high COL1A1 expression levels predicted hypoxia-modifying treatment benefit. Prognostic significance of COL5A2, FN1 and the ECM signature was dependent on patients harbouring TP53-mutations. Radiation alters the composition and structure of the ECM produced by MIBC. As a proof-of-concept, we showed that radiation-affected ECM genes are independent prognostic and predictive markers of radiotherapy benefit in MIBC. Future studies should validate these radiation-induced ECM changes in clinical samples, and explore the role of FLG in radioresistance
Using three-dimensional equieffective dose mapping to audit a methodology for calculating permitted doses for head and neck reirradiation
No full textBACKGROUND AND PURPOSE: Reirradiation is increasingly common, but accounting for prior dose to the spinal cord and brainstem is challenging. This study compares a simple isodose-based method of previous dose compensation with voxel-wise equivalent dose in 2 Gy fractions (EQD(2/2)) dose mapping to assess accuracy and safety. MATERIALS AND METHODS: Ten head and neck reirradiation cases were retrospectively reviewed. During planning, original dose distributions were mapped onto the reirradiation computed tomography scan. Isodoses within the cord and brainstem were used to segment dose-level substructures, with cumulative doses kept within defined tolerances. Following 3D EQD(2/2) mapping, the same cases were audited by recalculating cumulative maximum doses. Cumulative doses from both methods were compared. RESULTS: Retrospective EQD(2/2) analysis confirmed all cumulative doses were within tolerance, with up to 9.7 Gy difference between the two methods. In two cases, cord and brainstem doses approached tolerance. CONCLUSIONS: A simple, isodose-based approach to spinal cord and brainstem reirradiation tolerance calculation has been shown to be safe when retrospectively compared with voxel-wise EQD(2/2) mapping. This method can be implemented in any planning system capable of generating contours from isodose lines, offering a practical alternative where advanced EQD(2/2) dose accumulation software is unavailable
Patient-reported outcomes for patients with previously treated small cell lung cancer receiving tarlatamab: results from the DeLLphi-301 phase 2 trial
No full textINTRODUCTION: Tarlatamab demonstrated a durable response and promising survival outcomes in patients with previously treated small cell lung cancer (SCLC) in the phase 2, open-label DeLLphi-301 trial. Patient-reported outcomes (PROs) were evaluated to assess the benefit-risk profile of tarlatamab. METHODS: Patients received tarlatamab intravenously every 2 weeks at a dose of 10 mg (regulatory approved dose) or 100-mg until progression or loss of benefit. PROs, including European Organization for Research and Treatment of Cancer 30-item Quality of Life Questionnaire (EORTC-QLQ-C30) and 13-item lung cancer module (LC13), Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and the GP5 question of the Functional Assessment of Cancer Therapy - General Form (FACT-GP5), were collected at Cycle 1 (days 1, 8, 22), Cycle 2 (days 1, 15) and every 6 weeks from Cycle 3 onwards. PROs were summarized descriptively alongside the amount and reason for missing data and analyzed using a mixed model for repeated measures. In addition, median time to deterioration (TTD) for symptom and functional scales was analyzed. RESULTS: A total of 100 patients were PRO-evaluable at the selected target dose (10 mg). EORTC-QLQ-C30 and LC13 completion rates (proportion of PRO assessments expected to be completed) were high (> 80%) throughout the study. Least square mean changes from baseline showed a trend towards improvement for the QLQ-C30 subscale of global health status and stabilization for physical functioning. Patients experienced reduced symptom burden for dyspnea which was more pronounced for patients at later cycles (≥ 10 points), and stabilization for chest pain and cough. Median TTD exceeded 6 months for cough and dyspnea and was not estimable for chest pain. Overall, tarlatamab was well tolerated with the majority of patients reporting no bother or a little bit of bother from side effects post baseline. Patient-reported adverse events were generally of mild to moderate severity occurring rarely or occasionally. CONCLUSION: Alongside previously reported antitumor activity, tarlatamab demonstrated a positive benefit-risk profile in previously treated SCLC with favorable PROs across a range of functional outcomes and symptoms, while showing manageable and sustained tolerability. GOV NUMBER: NCT05060016
Efficacy of ketogenic metabolic therapy as an adjuvant to the current standard of care in the treatment of glioblastoma: a systematic review of clinical trials
No full textGlioblastoma is a diffuse, heterogenous tumour with a poor prognosis as current therapeutic options have limited efficacy. As a result, research aims to explore new treatment options which exploit the hallmarks of cancer. This review aimed to understand the breadth of research considering ketogenic metabolic therapy (KMT) as an adjuvant to standard therapy. KMT aims to improve overall survival by exploiting the metabolic reprogramming exclusive to neoplastic cells. Preclinical trials show benefits in KMT when used alongside radiotherapy, through increasing anti-tumour effects compared to controls. Literature searches conducted over three databases, in line with PRISMA guidelines, collated studies relevant to KMT and glioblastoma. Six prospective studies and one retrospective study met the inclusion criteria for this review. Data regarding participants, interventions and survival were extracted. Studies included used small numbers of participants, as many aimed to assess the feasibility of larger-scale trials, which increases errors and bias of results. Furthermore, direct comparison between trials was limited due to study heterogeneity, as each trial used differing parameters and diet compositions. As a result, no definitive conclusions could be made. Future studies should use larger cohorts with standardised parameters so results are representative, and comparisons can be made to evaluate efficacy
Brief report: post hoc validation of platinum ineligibility in NSCLC from the phase III IPSOS study
No full textINTRODUCTION: The phase III IPSOS study (NCT03191786) demonstrated that atezolizumab was associated with improved survival, stable patient-reported outcomes, and a favorable safety profile versus single-agent chemotherapy in patients with NSCLC ineligible for platinum-based chemotherapy. As no established consensus criteria for platinum ineligibility exist for NSCLC, we performed a post hoc analysis from IPSOS to evaluate clinical outcomes in a selected platinum-ineligible (sPI) population meeting a refined definition. METHODS: Patients with stage IIIB or IV NSCLC who were ineligible for platinum-doublet chemotherapy were randomized (2:1) to receive atezolizumab or single-agent chemotherapy (vinorelbine or gemcitabine). Patients in the sPI subgroup were defined as those with Eastern Cooperative Oncology Group performance status of 3, age older than 80 years, Eastern Cooperative Oncology Group performance status of 2 with relevant comorbidities, or age 70 years or older with relevant comorbidities. RESULTS: Of 453 patients from the IPSOS intention-to-treat population, 405 (89%) met sPI criteria. Compared with chemotherapy, atezolizumab improved overall survival (unstratified hazard ratio 0.78; 95% confidence interval: 0.63-0.98). Atezolizumab was associated with fewer grade 3 or 4 treatment-related adverse events (46 of 266 [17.3%] versus 46 of 134 [34.3%] with chemotherapy), grade 5 treatment-related adverse events (two of 266 [0.8%] versus four of 134 [3.0%]), and stabilization or improvement of patient-reported health-related quality of life. CONCLUSIONS: This subanalysis suggests that first-line treatment with atezolizumab provides long-term overall survival, consistent with the results from the intention-to-treat population, and a favorable safety profile compared with single-agent chemotherapy in the sPI population. In addition, the selection criteria for platinum ineligibility from the sPI population may provide a structured approach for treatment selection in NSCLC in clinical practice
Analyses on impact of tumor burden at progression and changes in IMDC from baseline in patients (pts) with advanced renal cell carcinoma (aRCC) treated with lenvatinib plus pembrolizumab (L plus P) in the phase 3 CLEAR trial
No full textProton therapy for vestibular schwannomas
No full textThis chapter discusses the treatment of vestibular schwannoma using proton beam therapy (PBT), which has been used in stereotactic radiosurgery, hypofractionated stereotactic radiotherapy, and fully fractionated radiotherapy. Using PBT, almost no dose is delivered beyond the proton Bragg peak, so compared to photon therapy the integral dose is reduced and less dose may be delivered to specific normal tissues, which may, in turn, reduce some acute and/or late toxicities. In PBT, however, there are additional uncertainties, including range uncertainty, which requires a larger 'safety margin' than is typically required for photon radiosurgery or hypofractionated stereotactic radiotherapy. The few published PBT series that describe patient outcomes are presented, all retrospective single center series, which do not suggest that local control or cranial nerve toxicity is more favorable than with photon therapy. Other toxicities, such as neurocognitive outcomes, risk of stroke, and radiation-induced malignancies, cannot be evaluated from the limited data. However, these series largely reflect now outdated treatment planning and delivery methods and do not include the latest Pencil Beam Scanning technology. It remains to be established whether outcomes with modern state-of-the-art PBT may be more favorable and whether particular subgroups, such as pediatric and young adult patients, may benefit
Phase I trial of ADP-A2AFP TCR T-cell therapy in patients with advanced hepatocellular or gastric hepatoid carcinoma
No full textBACKGROUND & AIMS: Patients with advanced hepatocellular carcinoma (HCC) generally experience poor outcomes despite current therapies, necessitating the development of alternative treatments. ADP-A2AFP is an investigational autologous T-cell therapy with an affinity-enhanced T-cell receptor (TCR) targeting alpha-fetoprotein (AFP). METHODS: We describe a phase I, open-label, first-in-human clinical trial of ADP-A2AFP (NCT03132792) in human leukocyte antigen-eligible participants with AFP-expressing HCC (or other tumor) not amenable to transplant/resection who progressed on, were intolerant to, or refused prior systemic therapy. Participants received lymphodepletion chemotherapy (cyclophosphamide 500 mg/m(2)/day for 3 days and fludarabine 20 mg/m(2)/day for 3 days, or cyclophosphamide 600 mg/m(2)/day for 3 days and fludarabine 30 mg/m(2)/day for 4 days) followed by ADP-A2AFP intravenous infusion. Safety evaluation was the primary objective; response per RECIST v1.1 was the key secondary endpoint. RESULTS: Twenty-one participants, 20 with advanced HCC and one with gastric hepatoid carcinoma received ≥1 ADP-A2AFP infusion. All participants experienced ≥1 grade 3 or higher adverse event; 52.4% experienced ≥1 grade 3 or higher event considered related to ADP-A2AFP treatment. Six participants experienced cytokine release syndrome (grade 1-2: n = 5; grade 4: n = 1). Best overall responses were complete response (n = 1), partial response (n = 1), and stable disease (n = 12); overall response rate was 9.5%. Eight patients had a stable disease duration of ≥16 weeks. Infiltration of ADP-A2AFP TCR and CD8+ T cells was seen in AFP-positive areas of post-treatment tumor samples. A relationship was demonstrated between increased ADP-A2AFP dose and serum AFP reduction in responders. CONCLUSIONS: Lymphodepletion chemotherapy followed by ADP-A2AFP TCR T-cell therapy showed a manageable safety profile and preliminary indications of antitumor activity in these previously treated patients. IMPACT AND IMPLICATIONS: Adoptive T-cell therapy could be a much-needed additional treatment strategy for advanced hepatocellular carcinoma. Clinicians and researchers interested in the development of adoptive T-cell therapies for advanced solid tumors will be interested to learn that in this phase I trial, ADP-A2AFP T-cell receptor T-cell therapy was associated with an acceptable benefit-to-risk profile and encouraging antitumor activity, illustrating the treatment potential of adoptive T-cell therapy for advanced hepatocellular carcinoma. GOV NUMBER: NCT03132792; first posted 2017-04-08
Emerging role of targeted therapies combined with radiotherapy in inoperable stages I to III NSCLC: a review from the IASLC ART subcommittee
No full textPrecision oncology has transformed the management of NSCLC by tailoring treatment to the specific genetic alterations driving oncogenesis. Targeted therapies, such as tyrosine kinase inhibitors, have been found to dramatically improve survival in patients with advanced-stage NSCLC. However, treatment options remain limited for patients with early or locally advanced stage (I-III) NSCLC harboring driver mutations, when the disease is not resectable, or the patient is unsuitable for surgery due to poor fitness or comorbidities. There is growing interest in combining targeted therapies with radiotherapy to optimize treatment outcomes for this patient group. Notably, a progression-free survival benefit has recently been reported with the third-generation tyrosine kinase inhibitor osimertinib in patients with inoperable, EGFR-mutated, stage III NSCLC after chemoradiotherapy. A narrative review of the literature was performed using PubMed, OVID (EMBASE), and ClinicalTrials.gov to identify studies evaluating the combination of targeted therapies and radiotherapy in inoperable stages I to III NSCLC. This review provides a comprehensive overview of the incidence of actionable driver alterations and emerging clinical evidence on combining targeted therapies with thoracic radiotherapy in patients with inoperable stages I to III NSCLC. The toxicity profile of combination treatments, optimal sequencing strategies, ongoing clinical trials, and future perspectives in this field are highlighted. In summary, a clear biological rationale supports the synergistic effects of combining targeted therapies with radiotherapy in the neoadjuvant, concurrent, and adjuvant settings. Advanced clinical trial methodologies may facilitate further research in this area, particularly for rare genetic alterations, to improve outcomes for these patients