|Non-small cell lung cancer||US|
|Non-small cell lung cancer||TBD|
Drug discovery research
We are currently working on an exploratory investigation of cancer immunotherapeutic drug candidates for developing a novel cancer immunotherapeutic drug. Our efforts include further therapeutic application of our tumor-associated antigen peptides (therapeutic drug seeds) to a different format from peptide vaccines. Concurrently, we are also studying tumor-associated antigens involving gene mutations (neoantigens), which have attracted increasing attention as a target for next-generation cancer immunotherapy, for clinical application based on our past experience in development of peptide vaccines and recent technological innovations.
ITK-1 (for prostate cancer)
- Personalized antigen peptide vaccination
- A phase III study is underway in Japanese patients with prostate cancer (currently under an observation period)
- Out-licensed to FUJIFILM Corporation.
Our lead candidate cancer peptide vaccine product, ITK-1, has been out-licensed to FUJIFILM Corporation. A phase III, double-blind, placebo-controlled, multicenter trial was initiated in Japan in June 2013, and the subjects are currently under an observation period.
This clinical study is being conducted in patients with prostate cancer, especially in patients with advanced castration-resistant prostate cancer who failed the conventional cancer therapies, including surgery, radiotherapy, hormone therapy, and/or chemotherapy prior to enrollment in the clinical trial.
ITK-1 is a personalized cancer peptide vaccine. Optimal antigen peptides will be selected for each individual patient from a set of 12 tumor-associated antigen peptides based on the results of immunity test using peripheral blood samples obtained from the patients prior to vaccination, and the selected peptides will be administered as a cancer vaccine. Additionally, prior to vaccination, preexisting immunity (i.e., immunological memory: adaptive immunity created after an initial response on the surface of cancer cells against certain type of peptide) are examined in each patient using our originally developed biomarker assay, and appropriate peptide antigens capable of inducing immunological memory were selected and used for vaccination. This procedure is based on the fundamental concept that vaccine antigens, to which the patients already possess antigen-specific immunological memory, are expected to cause quick and strong secondary immune responses after vaccination, resulting in better clinical outcomes. One of the challenges in the development of cancer peptide vaccines is a time lag from occurrence of immune responses to initiation of attacks of vaccine-induced CTLs on cancer cells and to gaining clinical effectiveness. We are trying to overcome this problem by our unique vaccination strategy to induce secondary immune responses using antigen peptides selected for each individual patient by our biomarker assay.
In our vaccination strategy, several peptide antigens are given at the same time. In cancer cells, expression of the genes relevant to the presentation of tumor-associated antigens may be altered to diminish or eliminate expression of the target molecules of the host immune system in order to avoid attack from that system. This is called “escape phenomenon” or “tumor immune escape”. Effectiveness of vaccination with a single-peptide antigen may initially be effective, but is more likely to be lost rapidly due to generation of mutations of the relevant genes in cancer cells. In contrast, it seems that there may be advantages of multiple-peptide vaccination in avoiding the escape phenomenon because of its antigenic variation, which may contribute to reducing the chance that the effectiveness of the vaccine is lost by generation of mutations in cancer cells.
GRN-1201 (for non-small cell lung cancer*1 and melanoma)
- Cancer peptide vaccine for the global market
- A U.S. phase I clinical study for the target indication of melanoma is underway
- A U.S. phase II clinical study for the target indication of non-small cell lung cancer is underway
GRN-1201 is a cancer peptide vaccine comprising a set of peptides capable of binding to HLA molecules of the phenotypes commonly found in American and European people.
This vaccine therefore could target wide market internationally, especially in the U.S. and Europe. We filed an Investigational New Drug (IND) application with the United States Food and Drug Administration (FDA) for the indication of melanoma in October 2015 and are enrolling patients with this disease in a phase I clinical study. We began a phase II clinical study in non-small cell lung cancer in the United States in January 2017. In these studies, GRN-1201 is coadministered with the immune checkpoint inhibitor anti-PD-1. Because of differences in immune functionality among patients, only 20% to 30% of patients with melanoma respond when treated with an immune checkpoint inhibitor alone. (Melanoma is thought to respond to these agents better than any other type of cancer.) Immune checkpoint inhibitors release the breaks on the immune system, and GRN-1201 is a cancer vaccine that boosts immune function. Administered together, these products have the potential to deliver a better therapeutic response by preventing cancer cells from evading the immune system and inducing the immune system to attack cancer cells.
GRN-1301 (for non-small cell lung cancer)
- Neoantigen*2 (Peptide vaccine targeting a drug-resistance-inducing gene mutation)
- Novel target to realize personalized medicine
We are developing a neoantigen peptide vaccine for an indication, non-small cell lung cancer. Many patients with lung cancers are already at an advanced stage or have metastasis at the time of their diagnosis, which leads to a poor prognosis. Approximately 220,000 individuals in the United States and 130,000 individuals in Japan reportedly develop lung cancers. More than 80% of patients with lung cancers are diagnosed with non-small cell lung cancer. Approximately 10% of non-small cell lung cancer patients (Japanese: 30%) have an EGFR*3 activation mutation (primary mutation), and for those patients, EGFR tyrosine kinase inhibitors (EGFR-TKI) are currently considered as the conventional and effective drug. However, many patients acquire resistance to EGFR-TKI within one to 1.5 years after the start of treatment, resulting in disease progression. It has been elucidated that a gene mutation, EGFR-T790M*4 point mutation (secondary mutation), occurs in approximately 60% of EGFR-TKI-resistant patients. We are developing a peptide vaccine against the EGFR-TKI-resistant gene mutation as the antigen (neoantigen).
T-iPS (for EB virus-induced*5 lymphoma)
- Regenerative immunotherapy using induced pluripotent stem cells derived from T lymphocyte (T-iPS cells)
- The world’s first clinical application of regenerative medicine in cancer immunotherapy
Based on the discovery made by Dr. Hiromitsu Nakauchi, Professor at the Institute of Medical Science, University of Tokyo, and Professor at Stanford University, et al., we are working on research and development of iPS technology-based regenerative medicine for the world’s first application in cancer immunotherapy. We are focusing on regeneration (rejuvenate) of T cells using iPS technology as a modality to prevent exhaustion of T cells that can attack cancer cells, which has been a challenge in cancer immunotherapy for many years, and to avoid adverse reactions associated with iPS cell therapy, which has also been regarded as another challenge. We are going to develop an application for a virus-induced blood cancer, EB virus-induced lymphoma, because it seems that it may be easier to demonstrate the concept of the product. We are also considering including other type of cancers which have larger market size, such as solid tumors, in the indications in the future.
【Explanation of terms】
- Non-small cell lung cancer (NSCLC): Lung cancers are generally divided into two main categories: small cell lung cancer (SCLC) and NSCLC. NSCLC progresses more slowly than SCLC, and tends to have a lack of response to chemotherapy or radiotherapy. In Japan, ≥80% of lung cancers are NSCLC. NSCLC is classified into more specific subtypes, including adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.
- Neoantigen: An antigen encoded by tumor-specific mutated genes (amino acid mutations). It is a cancer cell-specific antigen expressed after cancer cell-specific gene mutations occur in cancer cells of each individual patient, and does not exist in normal cells. Neoantigen is recognized as “non-self” by the immune system. Therefore, it is expected that neoantigen can be a promising target to efficiently induce cancer cell-killing immunity. Neoantigen may be useful as not only the antigen of cancer vaccines, but also a biomarker to identify the patients for whom an immune checkpoint antibody may be effective, as well as a precise target of T-cell therapies (CAR-T: chimera antigen receptor T-cell therapy, TCR-T: T-cell receptor therapy and T-iPS: iPS regenerative T cells), which are increasingly used in clinical practice.
- Epidermal growth factor receptor (EGFR): A receptor which can bind to epidermal growth factors to initiate signal transduction that is involved in the regulation of cell proliferation and growth. Activation of this receptor increases cell differentiation/proliferation. EGFR is expressed in many types of cells, and mutations in the EGFR gene may be associated with canceration of the cell and acquisition of migratory and invasive properties.
- EGFR T790M point mutation: A mutation of the 790th amino acid of EGFR protein from threonine to methionine. This mutation is considered to be associated with induction of resistance against the conventional tyrosine kinase inhibitors, such as Tarceva and Iressa.
- Epstein-Barr virus (EBV): EBV is a member of Herpesviridae family of viruses. Most people get infected with EBV, and in some people, it can be associated with tumor formation. This is the first virus detected in human tumors by Epstein and Barr in 1964.