Community Research and Development Information Service - CORDIS

FP7

IACT Report Summary

Project ID: 602262
Funded under: FP7-HEALTH
Country: Germany

Periodic Report Summary 2 - IACT (Immunostimulatory Agonist antibodies for Cancer Therapy)

Project Context and Objectives:
Immunostimulatory antibodies (IS-Abs) that activate the anti-tumor T-cell response by blocking inhibitory signals have shown significant clinical efficacy. The first of these so-called checkpoint blockers, anti-CTLA-4 Ab Ipilimumab, has been FDA-approved for treatment of metastatic melanoma in 2010 and is now widely applied as standard of care treatment. More recently, IS-Abs blocking the PD-L1/PD1 axis were shown to perform even better than Ipilimumab, not only in melanoma but also in other cancer indications (in particular lung and bladder cancer), and are expected to be approved for routine clinical application very soon.
While these clinical data are highly promising, it is also evident that only a fraction of patients show profound clinical responses to these checkpoint blockers and that a clinical response is often followed by tumor relapse. This notion points at the need for complementary drugs for stimulating the anti-tumor immune response through different mechanisms. Importantly, pre-clinical studies have shown that agonist IS-Abs that supplement stimulatory signals to activatory immune receptors can be at least as effective in inducing therapeutic anti-tumor immunity.
The aim of the IACT collaborative project is to boost the clinical development of agonist IS-Abs. Our starting point is the availability of a lead agonist anti-CD40 Ab that has already been tested in a phase I dose escalation study, and a series of candidate Abs targeting the immune receptors OX40 and 4-1BB.
The three-pronged IACT research strategy encompasses the following main objectives:
1. To drive further clinical development and testing of the available lead IS-Abs through:
o obtaining clinical proof of concept for the efficacy of anti-CD40 IS-Ab ChiLob7/4 in combination with chemotherapy in pancreatic cancer
o obtaining clinical proof of concept for the efficacy of anti-CD40 IS-Ab ChiLob7/4 with antigen-specific vaccination in human papillomavirus type 16 (HPV16+) head and neck cancer (HNSCC)
o providing state-of-the-art anti-OX40 and 4-1BB IS-Abs to be used for first in human testing
2. To optimally support the successful development of IS-Ab drugs through
o the identification of pharmacodynamics (PD) biomarkers that are related to therapeutic efficacy, and the development of validated, harmonized assays for their measurement in the context of clinical trials
o the development of validated, harmonized in vitro and in vivo models to guide the pre-clinical development of IS-Ab drugs and their best possible application in clinical trials
3. To set up a pipeline for the development of 2nd-generation IS-Abs with improved therapeutic index along four innovative approaches that are based on the latest insights in IS-Ab function as well as on proprietary technologies of our SME partners.

Project Results:
The lead anti-CD40 Ab will be tested in two clinical settings that reflect pre-clinical models in which striking impact on tumor and anti-tumor immunity has been observed. The first involves the application of anti-CD40 Ab in conjunction with gemcitabine chemotherapy in a neo-adjuvant setting in patients with resectable pancreatic ductal adenocarcinoma (PDA). The second involves combination of anti-CD40 Ab with an RNA-vaccine against the human papillomavirus type 16 oncoproteins E6 and E7 in HPV16-positive head and neck cancer (HNSCC).
In order to enable the clinical trials, new, optimized producer cells had to be generated for efficient production of the clinical-grade anti-CD40 Ab. Using these producer cells, a clinical batch of Ab (~500gr) has successfully been produced that is more than sufficient for the clinical studies planned. Same applies to the clinical batch of RNA vaccine to be used in the HNSCC study. The studies in HNSCC will start in January 2017, based on an approved trial protocol (EudraCT No. 2014-002061-30). In this initial phase, the patients will received RNA vaccine only. The studies with anti-CD40 Ab will start in Q3 2017, once QC on the clinical Ab batch has been completed and approval for the now finalized trial protocol (EudraCT No. 2016-000496-24) has been obtained.
Pre-clinical testing of the candidate Abs against OX40 and 4-1BB (20 each) has resulted in selection of two lead candidate, one for each target. Importantly, spin-off efforts of 2 partners outside of the immediate scope of the IACT consortium have resulted in novel Abs clearly superior to the already available ones. In view of the rapidly increasing competition around anti-OX40 and anti-4-1BB Abs, in particular the fact that several competitors have entered the clinic with several ‘regular’ Abs, it is essential that the efforts of the IACT partners focus on next-generation Abs with ‘first-in-class’ potential. Therefore, work on the previously selected lead antibodies will be suspended, and further activities will focus on the aforementioned newly-developed OX40 and 4-1BB Ab, on the dual-specific Abs that have been successfully developed in the context of the IACT program, as well as on the 4-1BB trimerbody concept.
While we had to adjust our efforts on OX40 and 4-1BB in view of the competition, our CD40 Ab activities as originally planned are still highly competitive. Development of novel, monospecific anti-CD40 Abs within IACT focuses on FcR-independent human-IgG2-formatted agonist antibodies (Southampton) and on newly generated, FcR-dependent glyco-optimized agonist antibodies (SME-partner Glycotope).
Pre-clinical experiments with surrogate anti-CD40 Abs in mouse tumor models have shown improved synergy with MEK-inhibitors as compared to chemotherapy (gemcitabine, temozolomide), which is mainly due to the fact that the MEKi have stronger impact on tumor growth while not affecting T-cell priming and effector function. This opens a path towards the development of treatment modalities in which agonist immunostimulatory Abs are effectively combined with targeted oncology drugs.

Potential Impact:
The key scientific impact of the IACT project will be the clinical application of a highly promising immunotherapeutic concept that has shown such tremendous potential in a multitude of pre-clinical studies from many independent laboratories. Considerable pre-clinical evidence shows that agonist immunostimulatory antibodies (IS-Ab) have equal or even greater immunotherapeutic potential than the ‘checkpoint’ blockers such as Ipilimumab. It is therefore essential to now push ahead – without further delay - in acquiring clinical proof of concept data. Only this will provide a path towards the further testing of agonist IS-Ab drugs in clinical studies with curative intent.
Clinical drug development and testing in patients is a time-consuming process, and consequently it is difficult to keep clinical development in line with a rapidly progressing pre-clinical pipeline. Improved drug concepts are often already conceived before their predecessors have been tested in the clinic. This is likely to be the case for agonist IS-Abs, in that the IACT partnership already has informed ideas of how to generate optimized, next-generation IS-Abs. With respect to the 1st generation of agonist IS-Abs, there has been an approx. 10-year delay in clinical development. In order to avoid another lag phase, IACT will push for immediate development of the next-generation compounds, based on the latest mechanistic insights and technologies. This is important, because it will still take at least 4-6 years before lead candidates resulting from this endeavour can be tested in first in human studies! In this manner, we will feed the drug development pipeline and can achieve continuity in the search for – and clinical testing of – immunotherapeutics.
The intended health impact of IACT is to develop new treatment options for pancreatic cancer and HPV16+ head and neck cancer, cancer types representing unmet medical needs that urgently require the development of more effective, non-surgical treatment options. Whilst the programme will concentrate upon the two tumour types in which our hypotheses can be addressed, it is important to emphasise that the reagents and know-how that comes from this work will have much wider relevance, potentially to the treatment of all cancers where evidence of immune recognition can be obtained.
The development of better treatment options for cancer patients is not merely dependent on creating a broader repertoire of drugs, it also requires a better understanding of the factors that govern the biological impact of a given drug when applied in a clinical study. It is therefore essential to identify pharmacodynamic (PD) biomarkers that can be used to provide insight into the ‘black box’ between drug administration and clinical efficacy versus failure (or alternatively: sub-optimal efficacy). Through PD-biomarker analysis one can learn whether a drug ‘hits’ its target (in the case of IS-Abs: the immune receptor) and whether this resulted in an appropriate response by immune cells.
Despite pioneering pre-clinical work by European laboratories, to date clinical development of cancer immunotherapeutics has so far been dominated by industry and by associated academic groups in the USA. By exploiting its unique competitive position on agonist IS-Abs, IACT aims at providing the mechanistic insights, pre-clinical and clinical evidence and tools sets, candidate pipeline, and second generation candidates necessary to accelerate this field within Europe to compete effectively.
With respect to the clinical testing and further development of agonist anti-CD40 IS-Abs, the efforts of the IACT consortium as planned originally are still state-of the-art and highly competitive in the field. In view of increasing competition with respect to Anti-OX40 and anti-4-1BB IS-Abs, we have adjusted our strategy concerning the development of these Abs by dropping the conventional Abs already available and concentrating on novel formats with ‘first-in-class’ potential that have been developed by the IACT partners.

List of Websites:
www.iact-project.eu

Contact

Rienk Offringa, (Head of Department)
Tel.: +49 6221423140
Fax: +49 621 42 2929
E-mail

Subjects

Life Sciences
Record Number: 195919 / Last updated on: 2017-03-14
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