• Keeping up with the hybrid magnetic resonance linear accelerators: how do radiation therapists stay current in the era of hybrid technologies?

      Eccles, Cynthia L; Campbell, M; Department of Radiotherapy, The Christie NHS Foundation Trust and Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK (2019)
      The benefits of integrating magnetic resonance imaging (MRI) into radiotherapy planning have long been extolled, first appearing in the literature as early as 1986. Most often described as a tool to be used when registered to a planning computed tomography to improve target and organ at risk delineation, the use of MRI for on-board image guidance and as a sole imaging modality throughout the entire radiotherapy pathway is quickly becoming a reality for appropriately selected patient populations in academic centres throughout the world. With the commercialization of these integrated magnetic resonance - radiotherapy delivery systems, an MRI-only workflow will prove beneficial, with MRI being used for treatment planning, localization, and on-treatment plan adaptation. Despite these technological advancements, recent surveys indicate uptake of MRI in radiotherapy as a routine practice has proven challenging. Reasons cited for this slow uptake were primarily related to health economics and/or accessibility. Furthermore, these surveys, like much of the academic literature, shy away from focusing on safe, sustainable staffing models enabled by comprehensive and appropriate education and training. In stark contrast to conebeam computed tomography guided therapy, magnetic resonance - radiotherapy systems are currently being operated by teams of physicians, radiographers, and physicists because of the diverse and complex tasks required to deliver treatment. The pace of innovation in RT remains high and unfortunately the window of opportunity to implement appropriate education continues to narrow. It is vital that we establish a framework to future-proof our profession. In the era of magnetic resonance-guided radiotherapy, we have yet to address the question of how to devise a consensus on the requisite knowledge, skills, and competence for radiation therapists and therapy radiographers using and/or operating MRI that provides guidance, without becoming prohibitively costly or time consuming.
    • Ketones and lactate increase cancer cell "stemness," driving recurrence, metastasis and poor clinical outcome in breast cancer: achieving personalized medicine via Metabolo-Genomics.

      Martinez-Outschoorn, U E; Prisco, M; Ertel, A; Tsirigos, A; Lin, Z; Pavlides, S; Wang, C; Flomenberg, N; Knudsen, E S; Howell, Anthony; et al. (2011-04-15)
      Previously, we showed that high-energy metabolites (lactate and ketones) "fuel" tumor growth and experimental metastasis in an in vivo xenograft model, most likely by driving oxidative mitochondrial metabolism in breast cancer cells. To mechanistically understand how these metabolites affect tumor cell behavior, here we used genome-wide transcriptional profiling. Briefly, human breast cancer cells (MCF7) were cultured with lactate or ketones, and then subjected to transcriptional analysis (exon-array). Interestingly, our results show that treatment with these high-energy metabolites increases the transcriptional expression of gene profiles normally associated with "stemness," including genes upregulated in embryonic stem (ES) cells. Similarly, we observe that lactate and ketones promote the growth of bonafide ES cells, providing functional validation. The lactate- and ketone-induced "gene signatures" were able to predict poor clinical outcome (including recurrence and metastasis) in a cohort of human breast cancer patients. Taken together, our results are consistent with the idea that lactate and ketone utilization in cancer cells promotes the "cancer stem cell" phenotype, resulting in significant decreases in patient survival. One possible mechanism by which these high-energy metabolites might induce stemness is by increasing the pool of Acetyl-CoA, leading to increased histone acetylation, and elevated gene expression. Thus, our results mechanistically imply that clinical outcome in breast cancer could simply be determined by epigenetics and energy metabolism, rather than by the accumulation of specific "classical" gene mutations. We also suggest that high-risk cancer patients (identified by the lactate/ketone gene signatures) could be treated with new therapeutics that target oxidative mitochondrial metabolism, such as the anti-oxidant and "mitochondrial poison" metformin. Finally, we propose that this new approach to personalized cancer medicine be termed "Metabolo-Genomics," which incorporates features of both 1) cell metabolism and 2) gene transcriptional profiling. Importantly, this powerful new approach directly links cancer cell metabolism with clinical outcome, and new therapeutic strategies for inhibiting the TCA cycle and mitochondrial oxidative phosphorylation in cancer cells.
    • Key communication skills and how to acquire them.

      Maguire, Peter; Pitceathly, Carolyn; Cancer Research UK Psychological Medicine Group, Christie Hospital NHS Trust, Manchester M20 4BX. peter.maguire@man.ac.uk (2002-09-28)
    • KEYLYNK-013: A phase 3 study of pembrolizumab in combination with concurrent chemoradiation therapy followed by pembrolizumab with or without olaparib versus concurrent chemoradiation therapy in patients with newly diagnosed limited-stage SCLC

      Rimner, A.; Lai, W. V. V.; Califano, Raffaele; Jabbour, S. K.; Faivre-Finn, Corinne; Cho, B. C.; Kato, T.; Yu, J. M.; Yu, L.; Zhao, B.; et al. (2021)
      Background: Concurrent chemoradiotherapy with etoposide and platinum (carboplatin/cisplatin) plus the anti‒PD-1 antibody pembrolizumab (pembro) has shown antitumor activity and acceptable safety in patients with limited-stage small-cell lung cancer (LS-SCLC). The poly (ADP-ribose) polymerase (PARP) inhibitor, olaparib, has shown clinical activity in combination with checkpoint inhibitors in patients with SCLC. KEYLYNK-013 (NCT04624204) is a randomized, placebo-controlled, double-blind phase 3 trial of pembro plus concurrent chemoradiation therapy followed by pembro with or without olaparib in patients with newly diagnosed LS-SCLC. Methods: Eligible patients are those aged ≥18 years with previously untreated LS-SCLC, ECOG PS 0/1, and adequate pulmonary function. Patients are randomized 1:1:1 to receive pembro 200 mg Q3W (groups A and B) or pembro placebo (saline) Q3W (group C) during the chemoradiation phase. All patients also receive 4 cycles of chemotherapy (etoposide 100 mg/m2 on days 1, 2, and 3 of each cycle and investigator’s choice of carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/m2 on day 1 of each cycle) with definitive thoracic radiotherapy (total dose of 45 Gy in 30 fractions twice daily over 3 weeks or 66 Gy in 33 fractions once daily over 6.5 weeks starting on day 1 of cycle 2). After chemoradiation, prophylactic cranial irradiation is strongly recommended for patients with CR/PR or at investigator’s discretion for patients with SD. Postchemoradiation patients receive pembro 400 mg Q6W plus olaparib placebo (group A), or pembro 400 mg Q6W plus olaparib 300 mg BID (group B), or pembro placebo plus olaparib placebo (group C) for 9 cycles/12 months. Randomization is stratified by ECOG PS (0 vs 1), SCLC stage (I/II vs III), radiation fractionation (twice vs once daily), and region (east Asia vs North America/western Europe/UK/Australia vs rest of world). Tumor imaging occurs at baseline, within 12 weeks of cycle 1 day 1, followed by Q9W to the end of year 2, Q12W in year 3, Q16W in year 4, every 6 months in year 5, and annually thereafter. Imaging is assessed per RECIST v1.1 by blinded independent central review. AEs are monitored from randomization to 30 days after cessation of study treatment (90 days for serious AEs) and graded per NCI-CTCAE v5.0. Health-related quality of life is assessed using EORTC-QLQ-C30 and QLQ-LC13. Primary endpoints are OS and PFS per RECIST v1.1 by blinded independent central review. OS and PFS are estimated by the Kaplan-Meier method. Between-group differences will be evaluated with stratified log-rank tests and Cox proportional hazard models with Efron’s method of tie handling. Secondary endpoints include ORR, duration of response, safety, and patient-reported outcomes. The study began enrollment in December 2020.
    • KEYNOTE-061: phase 3 study of pembrolizumab vs paclitaxel for previously treated advanced gastric or gastroesophageal junction (G/GEJ) cancer.

      Shitara, K; Özgüroğlu, M; Bang, Y; Di Bartolomeo, M; Mandalà, M; Ryu, M; Fornaro, L; Olesiński, T; Caglevic, C; Chung, H; et al. (2018-06)
    • KEYNOTE-086 cohort B: pembrolizumab monotherapy for PD-L1–positive, previously untreated, metastatic triple-negative breast cancer (mTNBC).

      Adams, S; Loi, S; Toppmeyer, D; Cescon, D; De Laurentiis, M; Nanda, R; Winer, E; Mukai, H; Tamura, K; Armstrong, Anne C; et al. (2018-02-14)
    • KEYNOTE-199 cohorts (C) 4 and 5: Phase II study of pembrolizumab (pembro) plus enzalutamide (enza) for enza-resistant metastatic castration-resistant prostate cancer (mCRPC)

      Hoimes, C. J.; Graff, J. N.; Tagawa, S. T.; Hwang, C.; Kilari, D.; Ten Tije, A. J.; Omlin, A.; McDermott, R. S.; Vaishampayan, U. N.; Elliott, Tony; et al. (2020)
      Background: Initial evidence suggests activity of pembro + enza in patients (pts) resistant to enza. We present results from the multicohort phase II study KEYNOTE-199 (NCT02787005) in chemotherapy-naive pts with mCRPC treated with pembro + enza after progression with enza and who had RECIST-measurable (C4) or bone-predominant (C5) disease. Methods: Pts who did or did previously receive abiraterone and for whom enza treatment failed after clinically meaningful response received pembro 200 mg Q3W, with continuation of enza for up to 2 y or until progression, toxicity, or withdrawal. End point was ORR per RECIST v1.1 (C4) by blinded independent central review (primary); DOR (C4), time to PSA progression, rPFS, OS, and safety. Results: A total of126 pts (C4, 81; C5, 45) were treated. Median (range) PSA was 31 ng/mL (0.4-1667) in C4 and 19 ng/mL (1-1750) in C5.Median (range) time from enrollment to data cut off was 15 mo (7-21) in C4 and 19 mo (7-21) in C5. In C4, ORR (95% CI) was 12% (6-22; 2 CRs, 8 PRs) and median (range) DOR was 6 mo (3+ to 13); 60% of pts had DOR ?6 mo. DCR (CR + PR + SD) was 51% in C4 and C5. Median (95% CI) time to PSA progression was 4 mo (4-4) in C4 and 4 mo (4-4) in C5. Median (95% CI) rPFS was 4 mo (3-6) for C4 and 4 mo (3-6) for C5; 12-mo rPFS rate was 17% in C4 and 23% in C5. Median (95% CI) OS was NR (16-NR) in C4 and 19 (14-NR) mo in C5; 12-mo OS rate was 70% in C4 and 75% in C5. Shorter median OS was more associated with prior enza treatment <6 mo than with prior enza treatment ?6 mo. Liver metastasis was associated with shorter median OS however, median OS in visceral disease subgroups appeared longer than expected. Any-grade/grade ?3 treatment-related AEs occurred in 75%/26% of pts in C4 and 69%/24% in C5. Two pts in C5 died of immune-related AEs (Miller Fisher syndrome and myasthenia gravis). Any-grade/grade 3/4 rash (regardless of relatedness) was higher than that in prior reports for individual agents (33%/6%). Conclusions: Pembro + enza after enza resistance had manageable safety and showed antitumor activity for RECIST-measurable and bone-predominant mCRPC. This combination is being evaluated in an ongoing phase III combination trial.
    • KEYNOTE-199 phase II study of pembrolizumab plus enzalutamide for enzalutamide-resistant metastatic castration-resistant prostate cancer (mCRPC): Cohorts (C) 4 and 5 update

      Omlin, A. G.; Graff, J. N.; Hoimes, C. J.; Tagawa, S. T.; Hwang, C.; Kilari, D.; Ten Tije, A. J.; McDermott, R.; Vaishampayan, U. N.; Elliott, Tony; et al. (2020)
      Background: We present results including time to cytotoxic chemotherapy and time to new anticancer therapy from the multicohort phase 2 study KEYNOTE-199 (NCT02787005) in chemotherapy-naive patients (pts) with mCRPC treated with pembrolizumab (pembro) + enzalutamide (enza) after progression on enza and whoResults: 126 pts (C4, 81; C5, 45) were treated. Median (range) PSA was 31 ng/mL (0.4- 1667) in C4 and 19 ng/mL (1-1750) in C5. Median (range) time from enrollment to data cut off was 15 mo (7-21) in C4 and 19 mo (7-21) in C5. In C4, ORR (95% CI) was 12% (6-22; 2 CRs, 8 PRs) and median (range) DOR was 6.3 mo (2.5+ to 13.4); 4 responders (73% by Kaplan-Meier estimation) had a response 6 mo. Efficacy analyses are displayed in the table. Grade 3 treatment-related AEs occurred in 26% of pts in C4 and 24% in C5. Two pts in C4 died of immune-related AEs (Miller Fisher syndrome and myasthenia gravis). Incidence of any grade/grade 3-4 rash (regardless of treatment relatedness) was higher than previously reported for individual agents (33%/ 6%) but manageable with standard of care treatments. Conclusions: Pembro + enza after enza resistance had manageable safety and showed antitumor activity for RECIST-measurable and bone-predominant mCRPC. This combination is being evaluated in the ongoing KEYNOTE-641 phase III trial (NCT03834493). had RECIST-measurable (C4) or bone-predominant nonmeasurable (C5) disease. Methods: Pts with or without prior abiraterone were eligible if they developed resistance to enza following prior response. Pts continued on enza and received pembro 200 mg IV Q3W for up to 2 y or until progression, toxicity, or withdrawal. End points: ORR per RECIST v1.1 (C4) by blinded independent central review (primary), DOR (C4), DCR, rPFS per PCWG3-modified RECIST, OS, time to cytotoxic chemotherapy, time to new anticancer therapy, and safety
    • Keynote-966 trial in progress: pembrolizumab added to gemcitabine and cisplatin for advanced biliary tract cancer

      Kelley, R. K.; Vogel, A.; Furuse, J.; Edeline, J.; Finn, R.; Ren, Z. G.; Su, S. C.; Malhotra, U.; Siegel, A. B.; Valle, Juan W; et al. (2020)
      Background: Biliary tract cancer (BTC), comprising intra- and extra-hepatic cholangiocarcinoma and gallbladder cancer, is a rare and aggressive malignancy. Most patients (pts) present with advanced or unresectable disease, for which the current standard of care is gemcitabine plus cisplatin. Median survival for these pts is only 12 inhibitor that has demonstrated modest antitumor activity as monotherapy in pts with previously treated BTC and has improved survival when used in combination with platinum-based chemotherapy in other cancer types. months, highlighting the need for more effective therapies. Pembrolizumab is a PD-1 inhibitor that has demonstrated modest antitumor activity as monotherapy in pts with previously treated BTC and has improved survival when used in combination with platinum-based chemotherapy in other cancer types.
    • Ki-67 index and response to chemotherapy in patients with neuroendocrine tumours.

      Childs, A; Kirkwood, A; Edeline, J; Luong, T; Watkins, J; Lamarca, Angela; Alrifai, D; Nsiah-Sarbeng, P; Gillmore, R; Mayer, A; et al. (2016-07)
      Chemotherapy (CT) is widely used for neuroendocrine tumours (NETs), but there are no validated biomarkers to predict response. The Ki-67 proliferation index has been proposed as a means of selecting patients for CT, but robust data are lacking. The aim of this study was to investigate the relationship between response to chemotherapy and Ki-67 in NET. We reviewed data from 222 NET patients treated with CT. Tumours were graded according to Ki-67 index: G1 ≤2%, G2 3-20% and G3 >20%. Response was assessed according to RECIST and survival calculated from start of chemotherapy to death. To explore Ki-67 as a marker of response, we calculated the likelihood ratio and performed receiver operating characteristic analysis. Overall, 193 patients had a documented Ki-67 index, of which 173 were also evaluable for radiological response: 10% were G1, 46% G2 and 43% G3; 46% were pancreatic NET (PNET). Median overall survival was 22.1 months. Overall response rate was 30% (39% in PNET vs 22% in non-PNET) and 43% of patients had stable disease. Response rate increased with grade: 6% in G1 tumours, 24% in G2 and 43% in G3. However, maximum likelihood ratio was 2.3 at Ki-67=35%, and the area under the ROC curve was 0.60. As reported previously, a high Ki-67 was an adverse prognostic factor for overall survival. In conclusion, response to CT increases with Ki-67 index, but Ki-67 alone is an unreliable means to select patients for CT. Improved methods to stratify patients for systemic therapy are required.
    • Ki-67 index in metastatic prostate cancer.

      Bryden, A A G; Freemont, Anthony J; Clarke, Noel W; George, Nicholas J; Department of Urology, Hope and Christie Hospitals, Manchester, UK. gbryden@hotmail.com (2001-12)
      OBJECTIVE: Prostate cancer in bone is generally thought to progress more rapidly than in its primary site, a supposition that is supported by studies of prostate-specific antigen velocity. However, descriptions of proliferative rates in metastases have relied on inferred data from in vitro studies of cell lines derived from metastases. The aim of this study was to determine directly the proliferative rate within bone metastases arising from prostate cancer. PATIENTS AND METHODS: 10 bone biopsies containing metastatic deposits of untreated prostatic cancer were obtained. These were immunohistochemically stained for the Ki-67 protein with the monoclonal antibody MIB-1, using the streptavidin-biotin complex technique. Benign prostatic tissue was used as the control. Using an image analyser, the Ki-67 index (% of cells staining positively) in each specimen was determined. RESULTS: In the 10 specimens the Ki-67 index ranged from 0.15 to 7.82%. Wide overlap was seen between groups of differing tumour differentiation. CONCLUSION: The proliferative rate as determined by the Ki-67 index in bone metastases of prostate cancer is similar to that reported in primary tumours. There does not appear to be a relationship between tumour grade and proliferative index in these specimens.
    • Killing of non-Hodgkin lymphoma cells by autologous CD19 engineered T cells.

      Cheadle, Eleanor J; Gilham, David E; Thistlethwaite, Fiona C; Radford, John A; Hawkins, Robert E; Cancer Research UK Department of Medical Oncology, University of Manchester and Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, UK. (2005-05)
      Adoptive immunotherapy with tumour-specific T cells is an emerging technology that may be applicable to a broad range of cancers. However, tumours can avoid T cell-mediated attack through multiple mechanisms including downregulation of major histocompatability complex (MHC). Consequently, engineering T cells to target intact protein antigen directly, thus bypassing the need for MHC presentation, can facilitate T cell targeting of tumour cells. Peripheral blood lymphocytes from nine of nine patients with non-Hodgkin lymphoma (NHL) were successfully gene-modified to express a receptor consisting of a CD19 single chain variable fragment (scFv) fused to the T cell CD3zeta signalling molecule. These T cells were functionally active against the CD19(+) Raji Burkitt's lymphoma cell line. Importantly, engineered T cells from seven of nine NHL patients efficiently lysed autologous lymph node tumour biopsy cells. There was a clear correlation between levels of CD19 expression on the tumour and effective killing by the engineered T cells. For two patients with a low or absent CD19(+) cells within the biopsy, no significant killing was observed. These results demonstrate that patients with CD19(+) NHL would be suitable candidates for this form of therapy in the setting of a phase I clinical trial.
    • The kinetics and specificities of deamination of nitrogenous compounds by X-radiation.

      Dale, Walter M; Davies, J V; Gilbert, Charles W; Christie Hospital and Holt Radium Institute, Manchester. (1949)
    • Kitchens as a source of Aspergillus niger infection.

      Loudon, K W; Coke, A P; Burnie, J P; Shaw, A J; Oppenheim, B A; Morris, C Q; Department of Medical Microbiology, Manchester Healthcare Trust, UK. (1996-03)
      In this study we investigated the epidemiology of a cluster of cutaneous infections owing to Aspergillus niger, which occurred in neutropenic patients in a bone marrow transplant unit. Heavy environmental contamination with the mould was found in the ward kitchen adjacent to the unit. The clinical and environmental isolates were typed by random amplification of polymorphic DNA (RAPD), which showed one of the patients was infected with the same strain as that isolated repeatedly from the kitchen area. In another case, contaminated stockinette material was implicated as the source of infection. Thorough cleaning of the ward kitchen resulted in no further cases on the unit. This highlights the fact that aspergilli may spread to patients by air, food or other vehicles, and underlines the importance of searching for a source and ensuring high levels of hospital hygiene are maintained.
    • Knowns and unknowns of bone metastases in patients with neuroendocrine neoplasms: A systematic review and meta-analysis

      Garcia-Torralba, Esmeralda; Spada, F.; Lim, Kok Haw Jonathan; Jacobs, Timothy; Barriuso, Jorge; Mansoor, Was; McNamara, Mairead G; Hubner, Richard A; Manoharan, Prakash; Fazio, Nicola; et al. (2021)
      Objective: This systematic review and meta-analysis aimed to develop an evidence-based summary of current knowledge of bone metastases (BMs) in neuroendocrine neoplasms (NENs), inform diagnosis and treatment and standardise management between institutions. Methods: PubMed, Medline, EMBASE and meeting proceedings were searched for eligible studies reporting data on patients with BMs and NENs of any grade of differentiation and site; poorly-differentiated large/small cell lung cancer were excluded. Data were extracted and analysed using STATA v.12. Meta-analysis of proportions for calculation of estimated pooled prevalence of BM and calculation of weighted pooled frequency and weighted pooled mean for other variables of interest was performed . Results: A total of 149 studies met the eligibility criteria. Pooled prevalence of BMs was 18.4% (95% CI 15.4-21.5). BMs were mainly metachronous with initial diagnosis of NEN (61.2%) and predominantly osteoblastic; around 61% were multifocal, with a predisposition in axial skeleton. PET/CT seemed to provide (together with MRI) the highest sensitivity and specificity for BM detection. Almost half of patients (46.4%) reported BM-related symptoms: pain (66%) and skeletal-related events (SREs, fracture/spinal cord compression) (26.2%; weightedweighted mean time-to-SRE 9.9 months). Management of BMs was multimodal [bisphosphonates and bone-modifying agents (45.2%), external beam radiotherapy (34.9%), surgery (14.8%)] and supported by little evidence. Overall survival (OS) from the time of diagnosis of BMs was long [weighted mean 50.9 months (95% CI 40.0-61.9)]. Patients with BMs had shorter OS [48.8 months (95% CI 37.9-59.6)] compared to patients without BMs [87.4 months (95% CI 74.9-100.0); p = 0.001]. Poor performance status and BM-related symptoms were also associated with worse OS. Conclusions: BMs in patients with NENs remain underdiagnosed and undertreated. Recommendations for management of BMs derived from current knowledge are provided. Prospective studies to inform management are required.
    • Konstantinos Logothetopoulos (1878-1961): the controversial life of an eminent gynaecologist.

      Iavazzo, Christos; Gkegkes, I; Gkegke, X; Karamanou, M; Androutsos, G; Gynaecological Oncology Department, Christie Hospital, Manchester, UK. (2015-02-20)
      Professor Konstantinos Logothetopoulos is considered one of the founders of modern Gynaecology in Greece.
    • KRAS G12C lung adenocarcinoma represents a distinct group of patients with different response to immunotherapy

      Masfarre, L.; Rocha, P.; Clave, S.; Moliner, L.; Navarro-Gorro, N.; Rios-Hoyo, A.; Sanchez, I.; Giner, M.; Corbera, A.; Taus, A.; et al. (2022)
    • KRAS: reasons for optimism in lung cancer.

      Lindsay, Colin R; Jamal-Hanjani, M; Forster, M; Blackhall, Fiona H; Division of Molecular and Clinical Cancer Sciences, University of Manchester, Manchester, UK (2018-06-09)
      Despite being the most frequent gain-of-function genetic alteration in human cancer, KRAS mutation has to date offered only limited potential as a prognostic and predictive biomarker. Results from the phase III SELECT-1 trial in non-small cell lung cancer (NSCLC) recently added to a number of historical and more contemporary disappointments in targeting KRAS mutant disease, including farnesyl transferase inhibition and synthetic lethality partners such as STK33. This narrative review uses the context of these previous failures to demonstrate how the knowledge gained from these experiences can be used as a platform for exciting advances in NSCLC on the horizon. It now seems clear that mutational subtype (most commonly G12C) of individual mutations is of greater relevance than the categorical evaluation of KRAS mutation presence or otherwise. A number of direct small molecules targeted to these subtypes are in development and have shown promising biological activity, with some in the late stages of preclinical validation.
    • KY1044 to target the ICOS pathways inducing intratumoral Treg depletion and agonism of effector T cells: Preliminary pharmacodynamic markers from a phase 1/2 multicenter trial

      Lin, C. C.; Naing, A.; Patel, M. R.; Burris, H. A.; Curigliano, G.; Thistlethwaite, Fiona C; Minchom, A. R.; Ascierto, P. A.; De Braud, F. G.; Eder, J. P.; et al. (2021)
      Background: Inducible T-cell co-stimulator (ICOS) is an important co-stimulatory receptor on effector T cells (Teffs) that also promotes tumor growth due to its high expression on regulatory T cells (Tregs). KY1044 is a fully human IgG1 that targets ICOS, acting via a dual mode of action (MoA) by depleting ICOShigh Tregs and stimulating ICOSLow Teffs. A Phase 1/2 clinical trial (NCT03829501) is currently assessing the safety and preliminary efficacy of KY1044, as a single agent and in combination with atezolizumab, in subjects with advanced relapsed/refractory malignancies. Using longitudinal blood samples and tumor biopsies, we aim to correlate KY1044 target engagement levels with pharmacodynamic (PD) properties (e.g. dual MoA) in the tumor microenvironment (TME) and the circulation. Methods: Phase 1 subjects were enrolled in dose escalation and enrichment cohorts to evaluate the effect of KY1044 as monotherapy (0.8 – 240 mg) Q3W and in combination (0.8 – 80 mg) with atezolizumab (1200 mg) Q3W. PBMCs, plasma and tumor biopsies were collected over the first 3 cycles to confirm target engagement and KY1044 MoA. The sample analysis included: immunohistochemistry (IHC) of tumor samples (ICOS, FOXP3 and CD8); circulating T cell immunoprofiling and receptor occupancy by chip-cytometry; PBMC and tumor sample pre- and post-treatment transcriptomic analysis; and the assessment of circulating cytokines (e.g. GM-CSF). Results: As assessed in PBMCs, full/prolonged ICOS target engagement on T cells was confirmed in subjects receiving a flat dose of 8 to 240 mg, while partial/transient saturation was observed at lower doses (0.8-2.4 mg). The target engagement was not affected by atezolizumab. The immune cell profiling showed changes in some populations, but there was no significant depletion of peripheral ICOS+ cells. In contrast, pre- and post-treatment IHC analysis of ICOS+/FOXP3+ cells in tumor biopsies confirmed a KY1044-dose dependent reduction of ICOS+ Tregs and maintenance of CD8+ T cells in the TME. Together, this resulted in an increased intratumoral CD8+/ICOS+ Treg ratio at all doses, plateauing from subjects receiving a flat KY1044 dose of 8 mg. KY1044-dependent agonism was indirectly assessed by measuring circulating cytokine levels. A post-dosing transient induction of GM-CSF was evident in subjects dosed with KY1044 at the 0.8 and 2.4 mg dose, whereas minimal induction was observed at dose of 8 mg and higher. Conclusions: LongitudinalPDdata confirmed the expected KY1044 MoA, namely ICOS Treg depletion and increased CD8/ICOS Treg ratio in the TME as well as T cell co-stimulation. The observed PD responses are currently being further explored in a more homogenous patient population.