Immunotherapies

Objective:
By developing advanced methods for prevention and therapy – immunotherapies, which are extremely efficient in treatment of cancer, allergies, and chronic degenerative disorders (Alzheimer disease), we aim to significantly improve the health state of the population, thus refining the quality of life, with the reduction of costs necessary for the medical services in elected diseases. One direction is to develop new diagnostic kits and better therapeutic methods for allergic disorders, based on specific recombinant epitopes. Fundamental research-derived knowledge in this field will subsequently serve to establish working and reproducible procedures which will guide GMP production of clinical-grade cells for further clinical trials. Within the OncoGen Center we aim to create a competent scientific nucleus, at European standards in personalized immunotherapy.

a) Innovative strategies for prevention, diagnosis and therapy of ragweed pollen induced respiratory diseases

Short description:
The main objective of the INSPIRED project is to develop a new diagnostic kit, based on recombinant allergen use, specific for ragweed allergic patients, which will better direct the therapy, with the support of an international team by attracting foreign specialists with recognized competence, thus increasing the Romanian participation in research areas at European level, and creating a scientific research core of specialists in advanced technologies based on recombinant allergens applications of European level within Oncogen.

By implementing the INSPIRED project, which addresses new thematic in the priority area, the Romanian research and economic competitiveness will increase, by virtue of development of high-throughput technologies based on recombinant allergens, which are nascent also in Europe. The design of hypoallergenic allergen derivatives using newly developed recombinant technologies will allow development of diagnostic tests based on recombinant allergens, useful in healthcare. The assays for allergen quantification can be implemented in the assessment of allergen loads in environmental samples and thus will help to improve forecasts of allergen exposure and thus contribute to improved allergen avoidance. Regarding the development of allergen-specific vaccines it is expected that the allergens needed for vaccination can be identified and that prototype molecules can be developed and used for clinical evaluation in follow-up projects conducted at European level including pharmaceutical industry.

The project will include the following activities:

  1. Characterization of the allergenic structures in ragweed pollen
  2. Expression of the panel of ragweed allergens as folded, wild-type-like allergens and generation of allergen-specific antisera
  3. Identification of the clinically most relevant allergens
  4. Development of recombinant allergen-based diagnostic tests
  5. Establishment of assays for the identification and quantification of ragweed allergens
  6. Study the effect of allergic co-sensitization to house dust mite (HDM) allergens on ragweed pollen allergy
  7. Development of innovative concepts for therapeutic vaccination and allergen-specific prevention

The expected outcomes of the project are therefore:

  1. Better understanding of the mechanisms of ragweed pollen allergy
  2. Development of recombinant allergen-based tests which will immediately improve patients care by providing tools to better prescribe and monitor existing ragweed SIT with allergen extracts
  3. Establishment of assays for the quantification of ragweed pollen allergens for i.) quality control of diagnostic allergen extracts ii.) quality control of therapeutic allergen extracts iii.) assessment of allergen exposure for allergen avoidance measures
  4. Identification of possible candidate molecules for improving immunotherapy of ragweed pollen allergy which can be evaluated in large scale follow up projects, within HORIZON 2020, attracting pharmaceutical companies active in the field of innovative biotechnology
  5. Exploration of the feasibility of preventive allergen-specific strategies

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b) Chimeric antigen receptor targeted oncoimmunotherapy using NK cells 

Short description:
Natural killer (NK) cells represent an attractive lymphocyte population for cancer immunotherapy due to their ability to lyse tumor targets without prior sensitization and need for human leukocyte antigens-matching, unlike T cells. Chimeric antigen receptors (CARs) represent a novel tool for development of adoptive immunotherapy by enhancing lymphocyte targeting and activation toward malignancies. CARs can be expressed in lymphocytes to create a large number of antigen-specific cells that upon recognition and binding to antigen-expressing tumor cells mediate cytotoxicity and cytokine production. The project proposed here will have a direct impact on the treatment of patients with currently non curable cancer in Romania and abroad. If successful, the project will result in a new, safe and effective treatment option for patients with currently unmet medical need. While the project aims to establish personalized cell based cancer treatment for patients with acute B cell leukemia by generating anti CD19 specific CARs, the technology can be easily expanded to other tumor antigens. Compared to T lymphocytes, we assume that retargeted NK cells will be especially suitable for the treatment of solid cancers as well. Especially for the solid cancers types that are abundant in Romania and which can become ideal targets, such as ovarian, colon, breast cancer and lung cancer. The targeting of specific tumor antigens will go along with the need for exact diagnosis and screening of suitable tumor antigens that are expressed by the patients’ cancer cells

The primary aim of the project is to follow a unique approach and to develop new CARs which are specifically suited for NK cell based therapies, which is cutting-edge in the field of anti-tumor personalized therapy. We expect that the project will yield international patent applications, which will ultimately translate into the commercialization of this technology in Romania and abroad. Fundamental research-derived knowledge in this field will subsequently serve to establish working and reproducible procedures which will guide GMP production of clinical-grade cells for further clinical trials. The project intends to create a competent scientific nucleus, at European standards in anti-tumor personalized immunotherapy, located within the OncoGen Center.

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c) Novel biomarkers and therapeutical strategies in immunosenescence and Alzheimer disease-associated immunosenescence (PNII-Idei, 259/2011, 2011-2016)

Short description:
Immunosenescence is defined as the progressive alterations appearing at the morphological and functional level into the immune system during the aging process.

The specific objectives of the present research project are:

  • Defining the immunosenescence status by introducing novel cellular biomarkers with specificity for this process.
  • Characterization of the proliferative potential, propensity for apoptosis and reactive oxygen species generating-capacity of the T cell subpopulation defined by the novel cellular biomarkers.
  • Defining the immunosenescence status by introducing novel serological biomarkers.
  • Defining the Alzheimer disease-associated immunosenescence in clinically diagnosed dementia and prodromal (pre-dementia) stages by introducing novel biomarkers for this pathology.
  • Exploring novel immunomodulatory therapeutic strategies in immunosenescence and Alzheimer disease-associated immunosenescence.

The expected impact of the present proposal is related to a significant development of the actual knowledge level regarding mechanisms and manifestations of immunosenescence and Alzheimer disease-associated immunosenescence. The projected applicative research directions are towards diagnosis and therapeutic strategies, the final deliverable products of the project being new diagnostic and therapeutic recommendations for these conditions.

Link: http://www.biothera.ro

Relevant publications:

  1. Groza S, Anghel S, Cristea M, Tatu C, Tanasie G, Panaitescu C, Gavriliuc O, Paunescu V, Bojin F. Telomere lenght changes in alzheimer disease. Fiziologia – Physiology, 2014; 24(82): 27-30.
  2. Groza S, Anghel S, Tatu C, Tanasie G, Panaitescu C, Gavriliuc O, Paunescu V, Bojin F. Lymphocytes Subsets Involved in Alzheimer Disease-Associated Immunosenescence. Fiziologia – Physiology, 2014; 24(81): 21-26.

d4cd4dFig.1. Graphic results for cell cycle analysis in young subjects/older subjects groups

d4ed4fFig.2. Senescence test for Alzheimer patients and control group

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