Cancer immunotherapy utilizes the body’s immune system to fight cancer. Immunotherapy is used to prevent cancer relapse and metastasis and to slow cancer progression by boosting the immune response through activation of various cells and molecules of the immune system. Three major cancer therapies are currently available: surgery, in which cancer lesions are surgically removed; radiotherapy, in which cancer cells are killed by irradiation; and chemotherapy (also known as anticancer drug therapy), in which cancer cells are killed using drugs. Cancer immunotherapy uses a novel approach and is expected to become “the fourth cancer therapy” for patients with cancer who failed conventional therapies.
Cancer peptide vaccines
In cancer immunotherapy, cytotoxic T lymphocytes (CTLs, also known as T cells) play a leading role in attacking cancer cells. The markers recognized by CTLs to distinguish between cancer cells and normal cells are called “tumor-associated antigens.” We are developing “cancer peptide vaccines” using tumor-associated antigen derived peptides (i.e., small fragments of tumor-associated antigen proteins).
Once our cancer peptide vaccine enters the body via injection, the tumor-associated antigenic peptides included in the vaccine would work to activate cytotoxic T lymphocytes (CTLs). Activated CTLs would then recognize the identical antigenic peptides presented on the surface of cancer cells and subsequently kill these cancer cells.
Unlike other immune system components, such as antibodies and B cells, T cells cannot directly recognize protein antigens. Protein antigens are fragmented into small antigenic peptides within the cell. These antigenic peptides then form a complex with human leukocyte antigen (HLA), and this complex is expressed on the antigen-presenting cell surface. These processed antigenic peptides serve as antigenic determinants for T cells (also called “T cell epitopes”), which are independent of higher order structure of their parent proteins, but which are determined by the intracellular processing of the parent protein and the binding affinity of the peptide to HLA. There are various types of HLA (polymorphism). Different HLAs specifically form a complex with different T cell epitopes. Tumor-associated antigens, which are derived from intracellular proteins of tumor cells, are recognized exclusively by CD8-positive CTLs. Intracellular proteins of cancer cells are ubiquitinated and transported to proteasomes, where the proteins are degraded into low-molecular-weight peptides. These resulting peptides, which are composed of 8 to 10 amino acid residues, are then transported to the endoplasmic reticulum (ER), where only peptides capable of binding to an HLA class I molecule form a peptide-HLA complex. The peptide-HLA complexes are then transported to the antigen-presenting cell surface. CTLs recognize these complexes via specific antigen receptors on their surface, called T cell receptors (TCRs).
Cancer cells express larger amounts of growth-related protein-derived peptides on their surface, as they grow more rapidly than normal cells. Cancer-specific peptides, also known as tumor markers, are also expressed on the surface of cancer cells. These peptides may be tumor-associated antigens targeted by CTLs.
Development of a cancer peptide vaccine involves the chemical synthesis of peptides with the same amino acid sequence as those presented on the surface of cancer cells. The chemically synthesized peptides are administered to cancer patients to activate and expand CTLs that specifically target and eliminate cancer cells presenting the peptides.
After administration, the synthetic peptides are phagocytosed by antigen-presenting cells such as macrophages and dendritic cells. The antigen-presenting cells then express the peptides complexed with HLA class I molecules on their surface. The antigen-presenting cells move to nearby lymph nodes and wait for CTL precursors that are specifically responsive to the peptide. When CTL precursors with receptors specific to the peptide migrate to the lymph nodes, they recognize the peptide complexed with HLA presented by the antigen-presenting cells, resulting in the activation and proliferation of CTLs. CTLs that have proliferated and matured travel through the lymph stream to reach the cancer lesion, where they confront cancer cells. Such mature CTLs can recognize peptides with the same amino acid sequence as the synthetic peptide (administered as vaccine) presented in a complex with HLA on the surface of cancer cell. On recognizing the peptide, CTLs are reactivated to induce apoptosis of the relevant cancer cells.
Comparison with other cancer vaccines
Ease of manufacturing and quality control
One of the main advantages of peptide vaccines is the ease of Good Manufacturing Practice (GMP)-compliant quality control, as the peptides used for our vaccine are chemically synthesized and are only around 9 amino acids long, with molecular weights of about 1,000 to 1,100. In addition, no raw materials of human or animal origin are required. This prevents viral contamination and eliminates the risk of BSE. Another advantage is the lower production cost.
Peptide vaccines also have significant clinical advantages. The use of protein preparations always requires special precautions against immediate-type allergy. Although one might think that peptide vaccines are unlikely to induce allergic reactions, because they are derived from self-proteins, the production of IgE antibodies against a number of self-proteins has been demonstrated. Such reactions are considered to be a cause of atopic disease. Vaccines using proteins or cells carry the risk of inducing allergic reactions. In contrast, most peptide vaccines are very unlikely to induce allergic reactions, since they contain antigenic peptides recognized by CTLs, but not those recognized by IgE antibodies, which mediate allergic reactions.
Induction of therapeutic effect
In addition to their clinical safety, peptide vaccines have advantages in terms of inducing therapeutic effects. Patients with cancer usually have decreased immunity because of increased production by cancer cells of transforming growth factor beta (TGF-β), and other immunosuppressive cytokines. Moreover, regulatory T cells are found in large amounts in cancer lesions. Induction of strong immunity is needed to overcome such aggressive immune suppression systems. For such induction, a sufficiently large amount of antigens have to be administered to the body. The required amount would be massive to an impractical extent, if parent protein antigens were used instead of peptide antigens at the same number of molecules, because parent protein antigens are much larger molecules than peptide antigens. The required amount would be even greater for cell vaccines.
Peptide vaccines have disadvantages compared with protein vaccines and other vaccines. Peptide vaccines are developed by narrowing down antigens used as vaccines for higher purity from the cell to protein level and then from the protein to the CTL epitope. Therefore, a cancer peptide vaccine developed for a patient with a certain type of HLA cannot be used for individuals with other types of HLA. This is because the peptide vaccine cannot bind to other types of HLA (HLA restriction), and the T cells can not recognize different HLAs. ITK-1 is composed of peptides compatible with the HLA-A24 molecule. Individuals with HLA-A24 are estimated to account for about 60% of the population in Japan.