Neoplasms

Digestive System Diseases

All Conditions

Rare Diseases

Stomach Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Stomach Diseases

Stomach Cancer

10 ml of whole blood is collected from each patient prior surgery Fresh tumor tissue samples (\~ 1cm3 ) are collected during surgery

ratio of predicted neoantigens

Long Vo Duy

This study is to develop methods for identification of neoantigens from patients with gastric cancer.

Gastric cancer (GC) is the fourth most common cancer type and one of the leading causes of cancer-related death in Vietnam. Immunotherapy using checkpoint inhibitors (CPI) in combination with certain types of chemotherapy has been clinically shown to offer survival benefits for patients diagnosed with advanced stomach cancer. However, clinical outcomes of CPI are associated with the quantity as well as the quality of neoantigens which arise due to mutations in coding regions of cancer associated genes. Such neoantigens can be presentable by cancer cells to the host adaptive immune system and activate antitumor responses. Hence, the identification of neoantigens would be of significance for immunotherapeutic approaches. Recent data published by the Tumor Neoantigen Selection Alliance (TESLA) indicate that a large proportion (98%) of predicted neoantigens are not immunogenic and ineffective in activating anti-tumor responses. In the present study, we aim to develop a comprehensive pipeline incorporating both computational prediction tools and experimental validation assays to enhance the accuracy of neoantigen identification.

Computational Prediction and Experimental Validation of Gastric Cancer Associated Neoantigens

The analysis of tumor DNA and RNA sequencing data will provide the mutational distribution of patients with gastric cancer, which could give rise to neoantigens. Of those, neoantigens derived from hotspot mutations in Vietnamese gastric cancer patients will be identified.

Computational pipelines will be employed to predict the pairing of neoantigens and HLA molecules. Subsequently, the ratio of those predicted neoantigens will be validated by co-immunoprecipitation with anti-HLA antibodies and mass spectrometry analysis for their binding to corresponding HLA molecules.

Immunoassays will be employed to identify neoantigens that could activate CD4 and CD8 T cells to kill tumor cells and serve as putative candidates for immunotherapy.

University Medical Center Ho Chi Minh City (UMC)

Colorectal Neoplasms

Intestinal Neoplasms

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Immunomodulating Agents

A single dose of pTTL will be administered after pre-conditioning chemotherapy with Fludarabine (30 mg/m(2) body surface area) x 3 and Cyclophosphamide (300 mg/m(2) body surface area) x 3 on days -7 to -5. pTTL will usually be infused on day 1 (5 days after last chemotherapy) with the option of administering it on day -3 if judged preferable based on the T cell expansion kinetics during pTTL production. pTTL is administered as a fresh product directly after production.

Dose escalation will be applied. Cohort 1 (1 patient): 1 million (with an accepted range of down to -5%) viable cells per kg body weight

Cohort 2 (3 patients): 2.5 million (down to -5%) viable cells per kg body weight

Cohort 3 (3 patients): 5 million (down to -5%) viable cells per kg body weight

Cohort 4 (remaining patients): up to 1 billion viable cells

pTTL is an autologous cell product for adoptive cancer immunotherapy containing in vitro expanded T cells stimulated with patient-specific tumour neoantigens derived from tumour-draining lymph nodes.

pTTL

Samuel Svensson, PhD

Andrea Salmén, MSE

Maximilian Kordes, MD, PhD

Mattias Carlsten, MD, PhD

Abbas Chabok, MD, PhD

Maziar Nikberg, MD, PhD

This is an open-label, non-randomised FIH trial investigating the safety and tolerability of a novel ATMP, pTTL, composed of autologous tumour-draining lymph node-derived T cells stimulated in vitro with personalised cancer neoantigens.

The neoantigens are selected through a process starting with next generation sequencing (NGS) of tumour material from the patient followed by selection of neoantigenic mutations using an in-house software, PIOR®. Selected neoantigen epitopes are expressed as recombinant proteins, NAG, and used to stimulate T cells to promote neoantigen-specific T cell expansion in vitro in pTTL production.

pTTL is thus based on autologous cells stimulated with patient-specific neoantigens. In consequence, every pTTL product is unique and designated for use in one single individual.

pTTL will be administered to patients with stage IV colorectal cancer (CRC) as a single intravenous dose.

STUDY RATIONALE The present trial is an open-label, non-randomised FIH trial investigating the safety and tolerability of pTTL, an immunotherapy consisting of autologous T cells activated and expanded in vitro using tumour-specific personalised neoantigens. The scientific rationale for pTTL relies on the fact that somatic mutations in tumour cells arising during malignant transformation result in altered proteins or peptides, so called neoantigens. Each individual tumour harbours multiple mutations that form a unique mutation profile, which enables personalisation of each therapeutic product. The neoantigens distinguish tumour cells from normal cells and make the tumour cells targetable by the immune system, and also allows targeting of several targets in the tumour simultaneously. In the present trial, up to 36 neoantigens will be targeted.

The starting material for pTTL is derived from tumour-draining regional lymph nodes (RLNs). The choice of this source of T cells is based on several advantages: The exposure to tumour antigens and, in the case of metastasis, tumour cells causes an enrichment of tumour- specific T cells. These T cells also have the potential to be superior to tumour-infiltrating T cells due to less exposure to tumour-mediated immunosuppression.

The production process for pTTL includes in vitro expansion, which increases the neoantigen-reactive T cell population. The selective T cell expansion is achieved by stimulation with protein constructs containing neoantigen epitopes, based on sequencing data from each patient's own tumour. This improves the chance of effective cancer cell eradication by both increasing the number of cells able to recognise and respond to the tumour, and by breaking immunological tolerance created in vivo by immunosuppressive mechanisms through activation in a non-suppressive environment.

PATIENTS The selected target group of the trial is adults with stage IV CRC. Patients may be considered eligible for inclusion if they have received treatments according to standard of care or if further standard of care treatment options are judged not to be in the patients' best interest (e.g. due to toxicity issues). Patients could also be eligible for inclusion in the trial during a scheduled pause in ongoing palliative therapy, at the discretion of the treating Investigator. Eligible patients must have a primary or metastatic lesion that is accessible to biopsy or surgery to obtain tumour material for NGS analysis. In addition, it is a requirement that the patient can undergo surgical excision of RLNs for use in pTTL production. Eligible patients should also have a good performance status (ECOG 0-1) and organ function, and no pre-existing conditionings deemed to increase their risk for severe side effects of pTTL therapy. Materials for Part I of the trial can be collected, while non-curative therapeutic options remain, and cryopreserved for later use if the patient should become eligible for inclusion in Part II.

METHODOLOGY The trial is composed of 3 parts, referred to as Part I, Part II and Part III.

Patients will be consented separately for Part I and for Part II/III: a first consent is given for tissue collection and pTTL production, and a second consent is given for pTTL treatment, including pre-conditioning chemotherapy and follow-up.

Part I of the trial entails patient identification, recruitment and screening of trial patients. It also comprises production of pTTL, which is performed in 3 steps:

1. Collection of tumour samples and normal samples for NGS and neoantigen selection. Production of stimulatory NAG-coupled beads raw material TC0301.
2. Collection of starting material for pTTL manufacturing from RLN.
3. pTTL manufacturing.

The time required from collection of tumour material and RLNs up until pTTL production and administration to the patient is approximately 8 to 12 weeks. The RLN starting material is cryopreserved after initial processing, enabling flexibility in the timing of pTTL administration.

Part II of the trial entails pre-conditioning and supportive care therapy, treatment with pTTL, and 26 weeks safety follow-up.

Pre-conditioning contains cyclophosphamide and fludarabine, and will be administered between Day -7 and Day -5 before scheduled pTTL administration. Supportive care treatment will start on Day -9 or Day -8. pTTL administration will normally be administered on Day 1, with the option of administration on Day -3 if cell expansion kinetics during pTTL production indicates this would be preferable. Part II will end when the last treated patient has been followed for 26 weeks or earlier in case of death or patient withdrawal.

Part III of the trial is a long-term follow-up initiated after completion of the initial 26 weeks safety follow-up period. Patients will participate in Part III for up to 4.5 years after end of Part II or until death, whichever comes first.

pTTL DOSAGE AND ADMINISTRATION The drug product (DP), i.e. pTTL, is composed of in vitro expanded RLN cells, enriched for neoantigen-specific T cells. It is formulated as a cell suspension with the excipients NaCl (9 mg/mL) and human serum albumin (25 mg/mL) in a transfusion bag intended for intravenous transfusion. The product is administered fresh. Each patient will receive a single administration of pTTL.The cell dose obtained during the manufacturing process will vary depending on the size of the neoantigen-reactive clones present in the starting material and their proliferative capacity. The minimum dose of a pTTL unit is 20 million viable cells and the maximum dose is 1 billion viable cells.

A First-In-Human Trial of pTTL in Advanced Colorectal Cancer

A First-In-Human, Phase I/IIa Trial of the Novel T Cell Immunotherapy pTTL in Patients With Advanced Colorectal Cancer

T cell receptor sequencing (TCRseq) will be used to characterise the pTTL product and to trace the identified pTTL clones in sequential peripheral blood samples post treatment.

If feasible, pre- and post-treatment biopsies will be taken for histological assessment of T cell infiltration and characterisation of tumour-infiltrating T cells.

Functional T cell assays (including but not limited to flow cytometry and cytokine release assays) will be used to evaluate neoantigen-specific responses in the pTTL product and in peripheral blood T cells, reflecting the extent of neoantigen reactivity in the different samples.

Serum tumour markers (the choice of markers will be made according to the patient's tumour characteristics) will be assessed as a biomarker of efficacy, as it reflects changes in tumour burden.

Circulating tumour DNA (ctDNA) will be assessed as a biomarker of efficacy, as it reflects changes in tumour burden.

Analysis of the pTTL product and of post therapy peripheral blood samples will be performed to evaluate the functional status, differentiation and lineage-identity of T cells and other immune cells. This is an exploratory outcome measure, where a large set of phenotypical aspects will be assessed in order to understand which characteristics are important for pTTL efficacy and potentially also to side effects. Evaluations of the T cells are performed using assays including, but not limited to, flow cytometry and RNA sequencing, to characterize the T cells with regard to identity, differentiation and functions which could be relevant to the efficacy of pTTL.

Data relevant for the correlation of neoantigen selection to clinical outcome will be stored and assessed. Aspects such as type of genetic alteration, variant allele frequency, RNA expression, and protein type and function will be considered and assessed in the context of clinical outcomes, signals of efficacy and biomarker evaluation. This is an exploratory outcome measure, and multiple assessments will be performed to better understand what neoantigen characteristics that could affect efficacy of pTTL.

To establish that pTTL can be administered to patients with advanced CRC without unacceptable toxicity. Adverse events (AEs) will be collected and assessed according to Common terminology criteria for AEs (CTCAE) v5.0. Special focus will be placed on immunological AEs and AEs known to be associated with T cell therapies, defined as AEs of special interest (AESI). AESI will include autoimmune reactions potentially resulting from off-target toxicity such as colitis, and immune-mediated reactions associated with immune cell activation, such as cytokine release syndrome (CRS).

Measured using radiology (including CT, MR or other applicable examination) and assessed according to iRECIST

The time between administration and documented objective response

The time from when an objective response is initially documented to the time of subsequent tumour progression.

The time to tumour progression after pTTL administration will be assessed using the iRECIST criteria and will take into account the time from inclusion in Part II of the trial until disease progression.

This measurement will be based on iRECIST, and will use radiological examinations (including CT, MR or other applicable examination) before and after pTTL administration in an endeavour to evaluate whether the progression kinetics of the patient's cancer is affected by pTTL administration

Defined as time from inclusion to death of any cause.

Defined as time from inclusion to tumour progression or death of any cause.

Defined as time from inclusion to death of disease.

CTC Clinical Trial Consultants AB

Karolinska University Hospital

Region Västmanland

Vecura

Neogap Therapeutics AB

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Carcinoma

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Endocrine System Diseases

Gonadal Disorders

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Ovarian Cancer

Ovarian Epithelial Cancer

Cherif Akladios, MD

Chérif AKLADIOS, MD, PhD

In 2020, epithelial ovarian cancer (EOC) accounts for 313,959 new cases and 207,252 deaths worldwide. The standardized 5-year net survival of a woman with EOC is 44% for cases diagnosed between 2005-2010. This is because 2 out of 3 cancers are found at an advanced stage with invasion beyond the ovaries to the entire peritoneum or distant metastasis. Treatment of EOC is currently based on platinum-based chemotherapy combined with paclitaxel and maximal cytoreduction surgery. Newer combination therapies may be introduced such as bevacizumab and oral poly ADP-ribose polymerase (PARP) inhibitors. Despite the combination of different therapeutic modes, the 5-year survival has not progressed much since the 1980s. The development of new and more effective therapies is essential but requires a better understanding of cancer heterogeneity and the identification of new therapeutic targets.

Cancer heterogeneity results from genetic and transcriptional variations between tumors but also between cells of the same tumor. This heterogeneity has an impact on the development of the tumor and its resistance to treatment. One of the methods to study this heterogeneity is single cell RNA sequencing (scRNAseq) which allows to analyze individually and simultaneously the gene expression (transcriptomics) of thousands of cells. Studies on EOC using this technique have already been performed but they were based on small numbers with very different tumor types and stages.

The objective of this protocol is to characterize by scRNA-seq the architecture and microenvironment of primary and secondary tumors of 50 patients with EOC at the single cell level and to correlate the data with the clinical characteristics of the patients, especially during recurrence and/or chemoresistance, in order to identify the molecular parameters allowing tumor cells to acquire survival, invasion, metastasis and chemoresistance capacity as well as to carry out the inventory of cell populations within the different sites of EOC. We will also analyze the interaction between tumor cells and the microenvironment, by studying on the one hand the involvement of immune cells in the antitumor response and on the other hand how tumor cells modulate the microenvironment to make it permissive to the development of the EOC. We will compare the data obtained for each patient with healthy tissue (from the same patient) in order to determine the common and specific tumor molecular signatures in EOC, the latter point allowing us to evaluate the intra and inter-patient variability. Similarly, the comparison of the transcriptomic profile of the same tumor subtype in several patients will allow us to determine if certain transcriptional perturbations are ubiquitous. The identification of these common pathways would allow the discovery of potential therapeutic targets.

Furthermore, the molecular processes leading to chemoresistance are still unknown. We will investigate whether known chemoresistance markers are present in tumor cells from primary sites and whether their presence correlates with the response to treatment in patients. We will also study the molecular mechanisms of resistance to treatment in our patients which will ultimately allow the development of new therapies. We will also try to find new prognostic markers which is made possible by the clinical follow-up of the patients.

The existence of this heterogeneity will be confirmed by complementary genetic analyses of the genome and exome (search for mutations, variation in gene copy number or chromosome copy number, epigenetic effects) by different molecular biology techniques (qPCR, NGS sequencing) and the markers that will be identified can be confirmed by histochemical analysis.

After tumor stage determination by the pathology department the fresh tumor samples will be prepared for the single cell preparation.. The samples will be transported in a cold transport solution (MACS Storage tissue, Miltenyi). These samples will be used for library preparation using the Chromium Controller (10X Genomics) and sequencing using the NextSeq550 system (Illumina) as well as for HLA-bound neoantigen identification by mass spectrometry. After data analysis by bioinformatics, we will study the transcriptome of each identified cell population. The identified markers will be confirmed by histochemical and molecular biological analysis.

Transcriptional Map of Ovarian Cancer at the Single Cell Level

We will study the cellular populations constituting ovarian tumors by comparing the existing cellular heterogeneity between patients (inter-patient) but also within the same patient, between primary and secondary sites on the one hand and within the same tumor tissue on the other hand (intra-patient) as well as the comparison with tissue considered as healthy between patients.

Neoantigens present on the surface of tumor cells will be isolated by immunoprecipitation from cell lysates and their nature will be determined by LC-MS/MS. These proteomic results will be compared to the transcriptomic results by single cell sequencing obtained in the main objective.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Computational Prediction and Experimental Validation of Gastric Cancer Associated Neoantigens	NCT05498194	Gastric Cancer Neoantigens	ratio of predic...	15 Years - 18 Years	University Medical Center Ho Chi Minh City (UMC)
A First-In-Human Trial of pTTL in Advanced Colorectal Cancer	NCT05908643	Colorectal Canc...	pTTL	18 Years -	Neogap Therapeutics AB
Transcriptional Map of Ovarian Cancer at the Single Cell Level	NCT05030805	Ovarian Cancer		18 Years - 80 Years	University Hospital, Strasbourg, France
Transcriptional Map of Ovarian Cancer at the Single Cell Level	NCT05030805	Ovarian Cancer		18 Years - 80 Years	University Hospital, Strasbourg, France
A First-In-Human Trial of pTTL in Advanced Colorectal Cancer	NCT05908643	Colorectal Canc...	pTTL	18 Years -	Neogap Therapeutics AB
A First-In-Human Trial of pTTL in Advanced Colorectal Cancer	NCT05908643	Colorectal Canc...	pTTL	18 Years -	Neogap Therapeutics AB

Spots Global Cancer Trial Database for neoantigens

Every month we try and update this database with for neoantigens cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for neoantigens

Every month we try and update this database with for neoantigens cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for neoantigens cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.