University of Helsinki Background
Clinical translation of cancer immunotherapies remains elusive since many patients fail to respond to current approaches. To overcome this challenge, immunotherapies must be engineered to target the specific vulnerabilities of each patient’s tumor. This greater degree of personalization can be achieved using neoantigens that direct the patient’s immune system to recognize the tumors, invoking a strong and highly specific anti-tumor response. Unlike tumor-associated antigens (TAAs), neoantigens are not encoded by the human genome and are therefore not displayed by major histocompatibility complexes (MHC) on healthy cells.
Personalized cancer immunotherapies that depend on the accurate identification of tumor neoantigens include autologous dendritic cell-based vaccines, neoantigen-specific antibodies, and neoantigen-coated oncolytic viral vectors. However, currently available neoantigen identification methods have significant limitations: they are time-consuming (weeks to months), laborious, expensive and inaccurate, as they rely on the prediction of MHC-mediated peptide presentation. Alternative direct chromatography-based detection techniques are available, but their requirement for tumor material far exceeds the quantities obtained in tissue biopsies, preventing clinical neoantigen analysis altogether. Moreover, very few laboratories are sufficiently equipped to identify neoantigens, which impedes research and development of novel neoantigen-based immunotherapies.
Unlocking the full potential of cancer immunotherapies therefore requires more accurate, sample-conserving and cost-effective methods to identify immunogenic neoantigens that will permit effective targeting to the patient’s tumor.
PeptiCHIP is a novel microchip-based solution that enables rapid, accurate, user-friendly and standardized tumor neoantigen identification from small tumor biopsies. By addressing the technological limitations that are a major hurdle for the clinical translation of cancer immunotherapies, it will offer more meaningful and cost-effective neoantigen identification for immunotherapy companies, clinicians and researchers. The technology is particularly valuable for those looking to validate antigens that can be used for the clinical development of dendritic cell-based therapies, T-cell receptor designs, monoclonal antibody creation, or as the coating of oncolytic viruses.
More specifically, PeptiCHIP captures tumor antigens and neoantigens. The captured antigens are sequenced and their abundance is characterized using Mass Spec. In contrast to existing techniques, PeptiCHIP is a closed system that requires as little as 1 000 tumor cells or 20 ul of dissolved tumor material and processes them within 1 hour, slashing the running costs from 4000 EUR to just 90 EUR per analysis. It is compatible with current tumor biopsy collection methods and identifies the neoantigens accurately from these very low sample amounts. Moreover, operating PeptiCHIP does not require special training, which reduces the need for trained biochemical personnel, and it can be easily incorporated into existing workflows. Furthermore, HEX (Homology Evaluation of Xenopeptides) is a software algorithm that has been developed to identify neoantigens from peptide sequences obtained using PeptiCHIP and to prioritize them based on their qualitative properties – namely by predicting their ability to bind MHC and their resemblance to known immunogenic peptides. HEX significantly improves the accuracy of neoantigen identification and reduces the number of false leads. In short, PeptiCHIP and HEX will accurately establish the complete tumor neoantigen repertoire after condensing neoantigen purification steps into a single chip, thereby facilitating the development of more personalized and efficacious cancer immunotherapies.
The preprint version of PeptiCHIP: a novel microfluidic-based chip platform for tumour antigen landscape identification under review at Nature Biotechnology is available via Research Square.
The manuscript on the HEX (Homology Evaluation of Xenopeptides) software algorithm is under review at Cancer Research Immunology.
Together with the HEX software algorithm for selection of the most promising neoantigens, PeptiCHIP has the potential to overcome the hurdles in the clinical translation of personalized cancer immunotherapies due to its innovative technical features:
Accuracy: precise identification of tumor neoantigen signatures is an absolute prerequisite for development of effective personalized immunotherapies. PeptiCHIP purification enables direct determination of neoantigen signatures, unlike the sequencing-based or other microarray chip-based technologies, which merely predict the peptide signature expressed on the tumor cell’s surface.
Speed: processes tumor material at an unparalleled rate – within 1 hour – compared with at least 48 hours for competing technologies.
Low sample requirement: no sample is lost in the closed system, in contrast to standard methods that involve a substantial loss of valuable tumor material due to multiple ultracentrifugation and chromatography steps. Since the requirement for tumor material is much lower compared to current state-of-the-art, PeptiCHIP is compatible with current clinical tumor biopsy practices.
Cost-saving: the running cost for PeptiCHIP-based analyses is significantly lower than that of the less accurate and cumbersome state-of-the-art.
Convenience: PeptiCHIP is easy to integrate into existing analysis workflows. It is quick and easy to use and does not require additional training or specialized biochemical personnel.
PeptiCHIP will standardize, streamline and improve the clinical translation of immunotherapies, and consequently benefit patients, researchers and the society as follows:
For the first time ever, PeptiCHIP enables the cost-effective development of entirely novel immunotherapies tailored to individual patients. Currently, neoantigens cannot be used to develop personalized treatments. In addition to generic tumor neoantigens, the device can identify new patient or cancer subset-specific neoantigens.
Novel target discovery and therapeutic development would be accelerated by the reduction in analysis costs and sample requirements of neoantigen repertoire elucidation. This would inevitably broaden and diversify the arsenal of personalized immunotherapies, particularly for tumors that have yet to benefit substantially from the advances in immunotherapy.
PeptiCHIP facilitates the enrichment of scientific knowledge and expertise regarding neoantigens. The standardization of neoantigen identification, coupled with the user-friendly nature of PeptiCHIP, would increase the number of laboratories capable of identifying neoantigen signatures, stimulating research into rendering tumors amenable to immunopharmacological manipulation.
Identification of tumor neoantigens has the potential to facilitate the discovery of druggable targets of clinical relevance. The principal hindrances have been the slow, cumbersome, and costly protocols that are currently used for identification of tumor neoantigens. PeptiCHIP overcomes these barriers by accelerating and streamlining the purification process in a cost-effective fashion.
The PeptiCHIP platform will offer more meaningful neoantigen identification for immunotherapy companies, clinicians, and researchers. The technology is particularly valuable for those looking to validate antigens that can be used for clinical development of DC-based therapies, TCR designs, monoclonal antibody creation, and as the coating of oncolytic viruses. PeptiCHIP has been validated with initial proof of concept data, there is a functioning prototype that has been piloted, and the team possesses solid competence in this field of science and commercialization.
In the short term, PeptiCHIP is an R&D tool that is easy to integrate into existing workflows by customers interested in analyzing and validating neoantigens. By using a fee-for-service business model, together with a product/kit as a consumable, the team can get involved in immunotherapy development collaborations, where the technology improves the clinical translation of immunotherapies. Moreover, the team can utilize the synergies with the professor’s research activities, namely the team’s ability to further improve our understanding of neoantigens, screen for highly immunogenic neoantigens in cancer subsets, and aggregate potentially highly valuable immunopharmacological data on neoantigens and TCRs for future commercial exploitation. In addition to immunopeptidomics applications, such database will also stimulate the generation of new health technologies to benefit people and society overall.
In the long term, PeptiCHIP is a platform technology to personalize immunotherapies. Functionally, it will become a kit for healthcare professionals to enable personalized therapies: the clinician will be able to take a small biopsy and utilize the PeptiCHIP technology to identify highly immunogenic antigens, which in turn can be tailored into the most appropriate therapy for the patient. Even if the technology might never reach a state of complete personalization, it is at least possible to stratify patients to enhance patient care and support clinical trials of novel therapeutics. Successful commercialization of PeptiCHIP can thus be an enabler of a true immunotherapy revolution.