Generation Of Clinical Trials Research Articles

Abstract C026: Single-cell multi-omics in pancreatic cancer reveals differential immune evasion mechanisms between prognostic groups

Abstract Pancreatic cancer has the worst survival of any human cancer with a 5 year survival of less than 10% with minimal treatment options. We have previously made the observation that patients with a T cell infiltrate in their primary tumor have a better prognosis then those that do not. To understand the nature of the immune infiltrate, we have in 12 patients performed 10X sequencing on CD45 cells from the tumor as well as single cell TCR-seq, BCR-seq and cite-seq and have performed the same experiment on the matching PBMCs. We have generated a dataset of approximately 185000 cells with half coming from the tumor. This unravels a complex immune infiltrate with the predominant immune cell types consisting of T cells. Our data shows that within the tumor infiltrate, patients either have high or low myeloid infiltration. We see a highly active Treg population that has multiple checkpoints activated. Using TCR data, we saw the biggest clonal expansions in CD8 EM, CD8 senescent cells and Tregs. Circulating TIL CD4 T cells are dominated by activated Tregs, Tfh, and Th2 and circulating TIL CD8 T cells are dominated by CD8 EM T cells. Our work identifies multiple novel therapeutic targets that should form the basis for rational design of a new generation of clinical trials in pancreatic ductal adenocarcinoma. Citation Format: Shivan Sivakumar, Ashwin Jainarayanan, Edward Arbe-Barnes, Enas Abu-Shah, Rachael Bashford-Rogers. Single-cell multi-omics in pancreatic cancer reveals differential immune evasion mechanisms between prognostic groups [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C026.

Patterns of metastatic spread and tumor burden in unselected cancer patients using PET imaging: Implications for the oligometastatic spectrum theory

Introduction and backgroundMetastatic disease has been proposed as a continuum, with no clear cut-off between oligometastatic and polymetastatic disease. This study aims to quantify tumor burden and patterns of spread in unselected metastatic cancer patients referred for PET-based staging, response assessment of restaging. Materials and methodsAll oncological fluorodeoxyglucose (FDG-) and prostate-specific membrane antigen (PSMA-) positron emission tomography (PET) scans conducted at a single academic center in 2020 were analyzed. Imaging reports of all patients with metastatic disease were reviewed and assessed. ResultsFor this study, 7,000 PET scans were screened. One third of PET scans (n = 1,754; 33 %) from 1,155 unique patients showed presence of metastatic disease from solid malignancies, of which 601 (52 %) and 554 (48 %) were classified as oligometastatic (maximum 5 metastases) and polymetastatic (>5 metastases), respectively. Lung and pleural cancer, skin cancer, and breast cancer were the most common primary tumor histologies with 132 (23.8 %), 88 (15.9 %), and 72 (13.0 %) cases, respectively. Analysis of the number of distant metastases showed a strong bimodal distribution of the metastatic burden with 26 % of patients having one solitary metastasis and 43 % of patients harboring >10 metastases. Yet, despite 43 % of polymetastatic patients having >10 distant metastases, their pattern of distribution was restricted to one or two organs in about two thirds of patients, and there was no association between the number of distant metastases and the number of involved organs. ConclusionThe majority of metastatic cancer patients are characterized by either a solitary metastasis or a high tumor burden with >10 metastases, the latter was often associated with affecting a limited number of organs. These findings support both the spectrum theory of metastasis and the seed and soil hypothesis and can support in designing the next generation of clinical trials in the field of oligometastatic disease.

Potentiation of natural killer cells to overcome cancer resistance to NK cell-based therapy and to enhance antibody-based immunotherapy.

Natural killer (NK) cells are cellular components of the innate immune system that can recognize and suppress the proliferation of cancer cells. NK cells can eliminate cancer cells through direct lysis, by secreting perforin and granzymes, or through antibody-dependent cell-mediated cytotoxicity (ADCC). ADCC involves the binding of the Fc gamma receptor IIIa (CD16), present on NK cells, to the constant region of an antibody already bound to cancer cells. Cancer cells use several mechanisms to evade antitumor activity of NK cells, including the accumulation of inhibitory cytokines, recruitment and expansion of immune suppressor cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), modulation of ligands for NK cells receptors. Several strategies have been developed to enhance the antitumor activity of NK cells with the goal of overcoming cancer cells resistance to NK cells. The three main strategies to engineer and boost NK cells cytotoxicity include boosting NK cells with modulatory cytokines, adoptive NK cell therapy, and the employment of engineered NK cells to enhance antibody-based immunotherapy. Although the first two strategies improved the efficacy of NK cell-based therapy, there are still some limitations, including immune-related adverse events, induction of immune-suppressive cells and further cancer resistance to NK cell killing. One strategy to overcome these issues is the combination of monoclonal antibodies (mAbs) that mediate ADCC and engineered NK cells with potentiated anti-cancer activity. The advantage of using mAbs with ADCC activity is that they can activate NK cells, but also favor the accumulation of immune effector cells to the tumor microenvironment (TME). Several clinical trials reported that combining engineered NK cells with mAbs with ADCC activity can result in a superior clinical response compared to mAbs alone. Next generation of clinical trials, employing engineered NK cells with mAbs with higher affinity for CD16 expressed on NK cells, will provide more effective and higher-quality treatments to cancer patients.

Toxicity profile and discordance between patients/physicians regarding niraparib maintenance in recurrent ovarian cancer (ROC) patients: Lessons from the NIQOLE real-life study—GINECO study.

5521 Background: Niraparib (NI) maintenance is a standard of care in platinum-sensitive ROC. Based on pivotal randomized trials, toxicity profile appears manageable through adapted drug dosing. However, data on tolerance and feasibility for unselected patients (pts) are missing, especially regarding pts’ reported adverse events (AE). Methods: NIQOLE study is a real-life longitudinal multicenter, phase IV study in ROC pts treated with NI maintenance. NI starting dose was adapted to pts’ weight and platelet count. The primary endpoint was to describe physicians’ reported AE (NCI-CTC-AE, grading from 0 to 5) leading to treatment modifications (TM), defined by dose reduction or treatment interruption/discontinuation from baseline to month 3 and delay of first TM. Secondary endpoints included duration of treatment and pts’ reported AE. Progression rates were exploratory endpoints. Owing to a digital device, pts provided remoted weekly AE (NCI PRO-CTC-AE, grading from 0 to 3) which were accessible to investigators. Concordance between the main symptomatic AEs reported by pts and those reported by physicians was analyzed. Results: 139 pts were treated: median age 70 [44-88], high-grade serous histology 91%, BRCA mutation 5%, first relapse 72%, prior bevacizumab 71%. The median delay from platinum-based regimen and NI was 49 days [15-109]. NI starting dose was 200 mg in 80% of pts and the median treatment duration was 5.6 months [0.2-21]. Progression rates at 3 and 6 months were 19 and 45%, respectively. At 3 months, 60% (n=84%) of pts had at least one TM, of whom 47% (n=66) were treatment-related AEs: dose reduction in 17/66 (26%), interruption in 53/66 (80%) and discontinuation in 11/66 (17%). The first AE inducing TM occurred at 22 days (median) [2 -91]. Thrombocytopenia was the main AE leading to TM (70% of cases). 24% of AEs were grade 3-4. Remoted PRO-CTC-AEs were acknowledged by physicians in 59% of cases of whom 31% led to adaptation of pts’ care. During the 3 months, 98% of pts reported symptomatic AEs (including nausea, constipation, fatigue, dry mouth and insomnia), of which 66% were grade 3. There was a very poor correlation (<0.20) between symptomatic AEs reported by the pts vs by the physicians (table). Conclusions: In real life, despite initial individual dosing, NI maintenance requires frequent TM during the first 3 months of treatment. There is a strong discrepancy between symptomatic AEs regularly captured by pts and those reported by physicians during clinics. Next generation of clinical trials should integrate pts' perspective to better assess toxicity and manage treatment course. Clinical trial information: NCT03752216 . [Table: see text]

Trimodality Treatment of Extremity Soft Tissue Sarcoma: Where Do We Go Now?

Extremity soft tissue sarcoma (ESTS) constitutes the majority of patients with soft tissue sarcoma (STS). Patients with localized high-grade ESTS > 5cm in size carry a substantial risk of developing distant metastasis on follow-up. A neoadjuvant chemoradiotherapy approach can enhance local control by facilitating resection of the large and deep locally advanced tumors while trying to address distant spread by treating the micrometastasis for these high-risk ESTS. Preoperative chemoradiotherapy and adjuvant chemotherapy are often used for children with intermediate- or high-risk non-rhabdomyosarcoma soft tissue tumors in North America and Europe. In adults, the cumulative evidence supporting preoperative chemoradiotherapy or adjuvant chemotherapy remains controversial. However, some studies support a possible benefit of 10% in overall survival (OS) for high-risk localized ESTS, especially for those with a probability of 10-year OS < 60% using validated nomograms. Opponents of neoadjuvant chemotherapy argue that it delays curative surgery, compromises local control, and increases the rate of wound complications and treatment-related mortality; however, the published trials do not support these arguments. Most treatment-related side effects can be managed with adequate supportive care. A coordinated multidisciplinary approach involving sarcoma expertise in surgery, radiation, and chemotherapy is required to achieve better outcomes for ESTS. The next generation of clinical trials will shed light on how comprehensive molecular characterization, targeted agents and/or immunotherapy can be integrated into the upfront trimodality treatment to improve outcomes. To that end, every effort should be made to enroll these patients on clinical trials, when available.

Report of consensus panel 7 from the 11th international workshop on Waldenström macroglobulinemia on priorities for novel clinical trials

Recent advances in the understanding of Waldenström macroglobulinemia (WM) biology have impacted the development of effective novel agents and improved our knowledge of how the genomic background of WM may influence selection of therapy. Consensus Panel 7 (CP7) of the 11th International Workshop on WM was convened to examine the current generation of completed and ongoing clinical trials involving novel agents, consider updated data on WM genomics, and make recommendations on the design and prioritization of future clinical trials. CP7 considers limited duration and novel-novel agent combinations to be the priority for the next generation of clinical trials. Evaluation of MYD88, CXCR4 and TP53 at baseline in the context of clinical trials is crucial. The common chemoimmunotherapy backbones, bendamustine-rituximab (BR) and dexamethasone, rituximab and cyclophosphamide (DRC), may be considered standard-of-care for the frontline comparative studies. Key unanswered questions include the definition of frailty in WM; the importance of attaining a very good partial response or better (≥VGPR), within stipulated time frame, in determining survival outcomes; and the optimal treatment of WM populations with special needs

Current state of developments and research of new candidate vaccines against tuberculosis (literature review)

147 literature sources on Tuberculosis vaccine, Vaccine prevention of tuberculosis were considered, 33 of them were studied in detail.According to the WHO report, 14 candidates for the TB vaccine are in clinical trials, including the AEC/BC02, Ad5 Ag85A and ChAdOx185A-MVA85A phase 1 vaccines, MTBVAC, ID93+GLA-SE, TB / FLU-04L and the GamB phase vaccine. 2a, amplifiers DAR-901, H56:IC31, M72/AS01, BCG revaccination and RUTI vaccine in phase 2b, VPM1002 and MIP/Immuvac in phase 3. Candidate TB vaccines vary in type and purpose.By type of vaccine are: subunit, vector, genetically modified live recombinant vaccines, live attenuated vaccines containing M. tuberculosis, inactivated vaccines.Subunit TB vaccines — contain purified immunoactive protein components isolated from M. tuberculosis with the addition of an adjuvant to enhance their immunogenic properties.Recombinant live vaccines — use a live vector to deliver heterologous antigens that elicit an immune response.Weakened live vaccines — contain a variant of a live pathogen that has been weakened to prevent serious disease when administered.Inactivated tuberculosis vaccines are designed to prevent and treat TB and are still being studied. These are vaccines with inactivated whole bacteria or their cleavage fragments, prepared physically or chemically.According to the purpose, vaccine candidates are studied in different target groups as pre- and post-exposure prophylaxis, in the context of anti-relapse prophylaxis and therapeutic vaccination, as well as to prevent the activation of LTBI in HIV-infected and contact persons.The results of recent clinical trials are important in addressing critical knowledge gaps and will clearly demonstrate the value of new TB vaccination strategies for endemic countries, and will shape the next generation of clinical trials.

Abstract IA022: Exploiting immune surveillance to target colorectal cancer evolution and mutability

Abstract The emergence of drug resistance limits the efficacy of targeted therapies in human tumors. Strategies to prevent or overcome resistance are essential to design the next generation of clinical trials. The prevalent view is that resistance is a fait accompli: when treatment is initiated, cancers already contain drug-resistant mutant cells. Notably, bacteria exposed to antibiotics transiently increase their mutation rates (adaptive mutability) thus improving chances of survival. We studied colorectal cancer (CRC) to assess whether tumor cells similarly exploit adaptive mutability to evade therapeutic pressure. We found that EGFR and BRAF inhibition activates stress-induced mutagenesis through downregulation of MMR and HR DNA repair effectors, and concomitant up-regulation of error-prone polymerases in drug-tolerant persister cells resulting in increased mutation rates. Overcoming drug resistance, therefore, means considering as a target not “only” individual oncogenes but also the evolving nature of human tumors. One possibility is to unleash the ability of the immune system to recognize mutations induced by therapy. We tested this possibility in syngeneic mouse models of CRC. Our findings indicate that inactivation of DNA repair mechanisms and manipulation of mutational loads can trigger immune surveillance and prolonged therapeutic responses. Citation Format: Alberto Bardelli. Exploiting immune surveillance to target colorectal cancer evolution and mutability [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA022.

Is it time to move on to the next generation of clinical trials in older patients with cancer?

Lung cancer is the leading cause of cancer death worldwide and is commonly diagnosed in older patients, with the median age of diagnosis in the UK being 71 years (IQR 62–75).1 Treatment rates, both curative and palliative in intent, decrease with age,2 the reasons for which are complex and might include complications in treatment delivery due to comorbidities, poor functional status, and frailty, which are common in older people. These problems might be more marked in squamous-cell lung cancer, which accounts for 25% of cases of non-small-cell lung cancer (NSCLC), as this type of lung cancer commonly arises in patients who are currently or have previously been smokers and might be associated with smoking-related diseases such as chronic obstructive pulmonary disease, ischaemic heart disease, and peripheral vascular disease.

Combination therapies involving checkpoint-inhibitors for treatment of urothelial carcinoma: a narrative review.

The implementation of immune checkpoint-inhibitors (CPI) has significantly improved the prognosis of a subgroup of patients with urothelial bladder cancer (BC). Still, the majority of patients will progress or experience a recurrence on CPI monotherapy. The next generation of clinical trials is now testing combination therapy with CPI and other agents that target different oncogenic mechanisms in an effort to improve efficacy. The beneficial toxicity profile of CPI but also the approval of CPI combinations in other cancer sites justifies their investigation also in BC. Here we report on clinical trials in muscle-invasive, locally advanced and metastatic BC combining CPI with other therapies, with a focus on the latest results presented at ASCO GU 2020, ASCO 2020 and ESMO 2019 as well as Phase-III trials currently ongoing. Multiple phase I-III clinical trials are investigating the combination of a CPI with a second CPI, with chemotherapy, or with targeted therapies like fibroblast growth factor receptor (FGFR) inhibitors or Nectin-4 inhibitors in different disease states. The results of more than 10 phase-III trials in advanced BC are eagerly awaited. Preliminary data are contradictory, as some trials released promising interim results, while others reported failure to achieve the primary endpoints. Taken together, combining CPI with other therapies is a logical and potentially promising approach, but it is too early to draw conclusions on specific combinations. As combinatorial therapies markedly increase the level of complexity, bedside-to-bench studies are warranted to gain deeper insight of underlying biological mechanisms which can be used to optimize future trials.

Glioblastoma: Emerging Treatments and Novel Trial Designs.

Simple SummaryNowadays, very few systemic agents have shown clinical activity in patients with glioblastoma, making the research of novel therapeutic approaches a critical issue. Fortunately, the availability of novel compounds is increasing thanks to better biological knowledge of the disease. In this review we want to investigate more promising ongoing clinical trials in both primary and recurrent GBM. Furthermore, a great interest of the present work is focused on novel trial design strategies.Management of glioblastoma is a clinical challenge since very few systemic treatments have shown clinical efficacy in recurrent disease. Thanks to an increased knowledge of the biological and molecular mechanisms related to disease progression and growth, promising novel treatment strategies are emerging. The expanding availability of innovative compounds requires the design of a new generation of clinical trials, testing experimental compounds in a short time and tailoring the sample cohort based on molecular and clinical behaviors. In this review, we focused our attention on the assessment of promising novel treatment approaches, discussing novel trial design and possible future fields of development in this setting.

Applications of Omics Technologies in Regenerative Therapies for Cardiac Repair

Lately, cardio regenerative therapeutic approaches in clinic have received strong boost from promising research advances in stem cells. Researchers have shown applications of the first generation of clinical trials using cell-based therapies in the heart that have been performed with bone marrow and adipose tissue derived mesenchymal stem cells shortcomings in the first generation cells. Second generation cell therapies are considered superior and being considered towards the use of cardiac-committed cell populations. These include cardiac progenitor cells and pluripotent stem cell derived cardiomyocytes. However, translating the research laboratory results along with pre-clinical data into effective clinical treatments is still thought to be challenging. This is due to the existing lack of knowledge on the regenerative mechanisms of action of these therapeutic products in addition to the stringent regulatory and safety concerns. This has prompted researchers to consider advanced analytical methods for characterization of such complex products and a deep understanding of their therapeutic effects at the cell and molecular level. This characterization is considered very critical to overcome the challenges and make these cells compatible with the advanced therapies. To this end, omics technologies including proteomics and glyco(proteo)mics that are based on state-of-the-art mass-spectrometry have shown tremendous promise to generate novel data on cell biology along with the required assessment of cell based-products that are applied in cardiac regeneration strategies. In this perspective, we have described proteomics and glyco(proteo)mics and discuss the impact of omics technologies on cardiac progenitor cells and pluripotent stem cell derived cardiomyocytes biology cardiac regenerative therapies.

Activated Regulatory T-Cells, Dysfunctional and Senescent T-Cells Hinder the Immunity in Pancreatic Cancer.

Simple SummaryPancreatic cancer has the worst survival of any human cancer. Checkpoint blockade has not yielded much benefit in pancreatic cancer. We explored immune cell phenotypes with this disease to identify new targets for checkpoint blockade therapy. We created a checkpoint-focused panel to analyse immune cells from eight pancreatic cancer patients. This showed us the majority of T-cells are senescent. Further T-cell investigation demonstrated the majority of cytotoxic T-cells have intermediate to low PD1 expression suggesting why PD1 may not work as a pancreatic cancer therapy strategy. Our data has also highlighted a regulatory T-cell population which is highly activated and can mediate immunosuppression. The checkpoints that are highly expressed on these cells are TIGIT, ICOS and CD39, suggesting inhibition of these may be a viable therapeutic strategy. Furthermore, we showed that Tregs were retained amongst the fibroblast stroma of the tumour. Our work suggests there are key checkpoints on Tregs that may help guide therapeutic strategies in pancreatic cancer.Pancreatic cancer has one of the worst prognoses of any human malignancy and leukocyte infiltration is a major prognostic marker of the disease. As current immunotherapies confer negligible survival benefits, there is a need to better characterise leukocytes in pancreatic cancer to identify better therapeutic strategies. In this study, we analysed 32 human pancreatic cancer patients from two independent cohorts. A multi-parameter mass-cytometry analysis was performed on 32,000 T-cells from eight patients. Single-cell RNA sequencing dataset analysis was performed on a cohort of 24 patients. Multiplex immunohistochemistry imaging and spatial analysis were performed to map immune infiltration into the tumour microenvironment. Regulatory T-cell populations demonstrated highly immunosuppressive states with high TIGIT, ICOS and CD39 expression. CD8+ T-cells were found to be either in senescence or an exhausted state. The exhausted CD8 T-cells had low PD-1 expression but high TIGIT and CD39 expression. These findings were corroborated in an independent pancreatic cancer single-cell RNA dataset. These data suggest that T-cells are major players in the suppressive microenvironment of pancreatic cancer. Our work identifies multiple novel therapeutic targets that should form the basis for rational design of a new generation of clinical trials in pancreatic ductal adenocarcinoma.

Pragmatic approaches to the next generation of clinical trials in heart failure.

Pragmatic approaches to the next generation of clinical trials in heart failure.

Rumo a uma nova geração de ensaios clínicos: Pesquisa-ação Participativa em Saúde

A Pesquisa-ação Participativa em Saúde (PaPS) é uma abordagem que inclui as pessoas no processo. Não é feita "nas" pessoas como sujeitos passivos que fornecem "dados", mas "com" elas para fornecer informações relevantes no sentido de melhorar as suas vidas e produzir soluções. O processo de pesquisa é visto como uma parceria com as pessoas cuja vida ou trabalho é o tema da pesquisa. A PaPS é uma proposta promissora para uma nova geração de ensaios clínicos, sobretudo em estudos de base comunitária pois produz evidência para fazer face a diversos desafios atuais como o uso de tecnologias emergentes de saúde e estratégias de envolvimento de pacientes/comunidade para cocriarem soluções úteis assim como a gestão dos dados e a emergência da epidemiologia participativa.

Abstract IA13: Tracking and targeting colorectal cancer evolution

Abstract When metastatic cancers are challenged with targeted agents, almost invariably a subset of cells insensitive to the drug emerges. As a result, in most instances, targeted therapies are only transiently effective in patients. Strategies to prevent or overcome resistance are therefore essential to design the next generation of clinical trials. How can we overcome the near certainty of disease recurrence following treatment with targeted agents? Addressing this question means considering as a target not “only” individual oncogenes but also the evolving nature of human tumors. We used colorectal cancer (CRC) as a model system to test the hypothesis that by understanding tumors’ evolution, the emergence of drug resistance can be controlled. We find that clonal dynamics can be monitored in real time in the blood of patients, and liquid biopsies can be used to intercept the emergence of resistant clones before relapses are clinically manifest. We discovered that a multistep clonal evolution process driven by progressive increases in drug fitness underlies the development of resistance in cells and patient avatars. To have long-term efficacy, the use of targeted therapies must take into account the continuous evolution of cancer cells, that is to say, therapies must adapt to tumor evolution. One possibility is to anticipate the changes the tumors will make. For example, by knowing in advance how CRC cells overcome resistance to EGFR blockade, we devised further rounds of therapy. These findings became the bases of clinical trials aimed at targeting cancer evolution and exploiting liquid biopsies to monitor the emergence of drug resistance and to design further lines of therapies. Citation Format: Alberto Bardelli. Tracking and targeting colorectal cancer evolution [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr IA13.

Personalized treatment in metastatic triple-negative breast cancer: The outlook in 2020.

Compared with other breast cancer subtypes, patients with triple-negative breast cancer (TNBC), and irrespective to their disease stage, were always recognized to have the worst overall survival data. Although this does not seem different at the present time, yet the last few years have witnessed many breakthrough genomic and molecular findings, that could dramatically improve our understanding of the biological complexity of TNBC. Based on genomic analyses, it was consistently evident that TNBC comprises a heterogeneous group of cancers, which have numerous diverse molecular aberrations. This-in return-has provided a platform for a new generation of clinical trials using many innovative therapies, directed against such novel targets. At the present time, two PARP inhibitors and one anti-PD-L1 monoclonal antibody (in combination with chemotherapy) have been approved in certain subpopulations of metastatic TNBC (mTNBC) patients, which have finally brought this disease into the era of personalized medicine. In the current review, we will explore the genomic landscape of TNBC, through which many actionable targets were graduated. We will also discuss the results of the key-practice changing-clinical studies, and some upcoming personalized treatment options for patients with mTNBC, that may be clinically adopted in the near future.

Abstract A075: SPECTA: The EORTC translational research platform for Europe

Abstract SPECTA is the translational research platform from the European Organisation for Research and Treatment of Cancer (EORTC), which facilitates pan-European research projects by providing a comprehensive infrastructure: a single protocol and Patient Informed Consent to enrol patients with cancer, a centralised database for clinical data collection (including long-term follow-up and quality of life), a centralised biobank and quality control sample workflow, expert molecular laboratories dedicated to the needs of the translational research projects. So far, 11 countries with 36 sites are open for recruitment with 43 authorized investigators. Two SPECTA projects focus on rare populations. The first, AYA (Adolescent and Young Adults) enrols patients aged between 12 and 29 years old, diagnosed with high grade glioma or sarcoma. AYA is a pilot study with a strong collaboration, between DKFZ and EORTC, aiming at diagnosis confirmation (central pathology review by pathologist experts and methylation diagnosis), and extensive molecular analysis (WES, RNAseq and methylation array). The aim is not only to have a direct impact on patients through the clinical advice provided to the treating physician by the molecular tumor board, but also to build knowledge for future clinical trials in this population with unmet needs. The second, Arcagen, is a collaborative project with the EUropean network for RAre CANcer (EURACAN), the European network for rare cancer. This project, with the support of Roche, aims at building a clinically annotated genomic database (NGS panels for FMI) of 1,000 rare cancer patients from the 10 EURACAN domains. So far, 81 patients have been recruited: sarcoma (n=43), thymic malignancies (n=16), germ cell tumor (n=10), and rare head and neck tumor (n=15). Druggable alterations were found in about 15% of patients. Molecular reports will be sent to local clinicians, the study results will be used for designing for the next generation of clinical trials in adult rare cancers. The last project currently enrolling in SPECTA is IMMUcan, an Innovative Medicine Initiative project. IMMUcan will generate broad molecular (WES and RNAseq) and cellular profiling data (multiplex immunofluorescence and imaging mass cytometry) of tumor and its microenvironment. Integration of this information with clinical data, will promote understanding on how the immune system and tumors interact, and the impact of current therapeutic interventions. For this purpose, we will enrol 3,000 patients with NSCLC, HNSCC, breast, colorectal and renal cell cancers. For all projects, we faced recurrent issues regarding tumor and peripheral sample quality. We overcomed those issues by performing optimization studies for pan European collection of biological material (such as PBMCs, ctDNA, vesicles or FFPE slides stability for imaging). SPECTA is an academic solution for next level precision medicine, with all the clinical, operational and scientific challenges that it implies. Citation Format: Marie Vinches, Teresa de Rojas, Aleksandra Stevovic, Martin Mccabe, Jean Yves Blay, Vassilis Golfinopoulos, Sabine Tejpar, Marie Morfouace. SPECTA: The EORTC translational research platform for Europe [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A075. doi:10.1158/1535-7163.TARG-19-A075

Community and academic partnerships: Moving a new generation of clinical trials in NCI Community Oncology Research Program (NCORP) into community oncology practices.

2551 Background: NCORP is a model program that bridges academic and community oncology practices and research. Over the past decade, community cancer investigators have adopted new technology, encountered new treatment sequalae, and faced rising cost of care with its financial toxicity imposed upon individuals seeking care. Opportunities are abundant for community investigators to assess feasibility and uptake of research advances into community practice settings, yet these opportunities are met with the challenges of dynamic changes in types of organizations delivering cancer care and diversity of populations within their catchment areas. Little information is shared about how and to what extent the health environment influences this partnership and the implementation of a broad cancer research portfolio. Methods: This abstract reports on the continued interest and participation of community oncologists in research which is demonstrated by 987 practices with over 4000 investigators in NCORP. Since 2014, over 30,000 individuals enrolled in symptom management, screening, surveillance, quality of life, and treatment trials. An additional 4500 patients and clinicians have enrolled in care delivery studies. Results: NCORP has been central in evaluating the most effective strategies for investigators to effectively communicate to patients the science of genomically-driven trials. It has also provided ways of bringing the pediatric and AYA patients access to the most up-to-date treatment strategies and new therapies in their community. This creates the least disruption on family structure/dynamics, diminished traveling requirements/costs, and reduced the financial burden. NCORP promotes involvement of treating oncologists in research activities. This also improves care for patients not enrolled in clinical trials. Therefore, NCORP serves as a laboratory to determine the most effective strategies for co-management of cancer patients and survivors. Conclusions: Several questions however remain to be addressed using this clinical trial model. These include: how to continue to reduce disparities in cancer care and clinical trial participation; and, what are the best strategies for fostering implementation of cancer care models in community practice.

Abstract IA18: Inactivation of DNA repair to improve immune surveillance

Abstract When metastatic cancers are challenged with targeted agents almost invariably a subset of cells insensitive to the drug emerges. As a result, in most instances, targeted therapies are only transiently effective in patients. Strategies to prevent or overcome resistance are therefore essential to design the next generation of clinical trials. How can we overcome the near-certainty of disease recurrence following treatment with targeted agents? Addressing this question means considering as a target not “only” individual oncogenes but also the evolving nature of human tumors. We used colorectal cancer (CRC) as a model system to test the hypothesis that by understanding tumor’s evolution, the emergence of drug resistance can be controlled. We find that to have long-term efficacy, the use of targeted therapies must take into account the continuous evolution of cancer cells, that is to say, therapies must adapt to tumor evolution. Another approach is to unleash the ability of the immune system to recognize drug resistant cells. We tested this possibility in syngeneic mouse models of CRC sensitive to targeted therapies. Our findings indicate that inactivation of DNA repair mechanisms and manipulation of mutational loads can trigger immune surveillance and prolonged therapeutic responses. We postulate that rationally combined targeted and immuno-therapies can restrain tumor evolution, and can limit the emergence of drug resistance thus leading to long-term responses. Citation Format: Alberto Bardelli. Inactivation of DNA repair to improve immune surveillance [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr IA18.