Individualized cancer immunotherapy

Cancer is characterized by an accumulation of genetic alterations. A tumor may acquire up to thousands of different somatic mutations during the process of initiation and progression. A smaller number of cancer mutations interfere with normal cell regulation and help to drive cancer growth.[5]

Somatic mutations in the tumor genome can cause tumors to express mutant proteins (neoantigens) that are recognized by autologous T cells as foreign and constitute cancer vaccine targets.[2][6] Tumor Mutational Burden (TMB, the number of mutations within a targeted genetic region in the cancerous cell's DNA) have been thus suggested to correlate with patient survival post immunotherapy, although the findings are disputed.[7][8][9]

Such neoantigens are specifically expressed by tumor tissue and are not found on the surface of normal cells. They can upregulate tumor-specific T cells in patients without killing normal cells.[10]

T cells are key effectors of anticancer immunity. They are capable of distinguishing tumor cells from normal ones by recognizing HLA-bound cancer-specific peptides.[10] A requirement for the recognition of neoantigens by the immune system is that the neoantigens and their antigenic determinants, the neoepitopes, are processed and presented by human leukocyte antigen (HLA) molecules.[5] These molecules may be recognized by CD8+ cytotoxic T lymphocytes as foreign neoepitopes and, with the help of CD4+ T lymphocytes, trigger an immune response leading to tumor-specific killing.[4] CD8+ T cells are specialized for direct tumor cell killing. CD4+ T cells can interact with antigen-presenting cells such as dendritic cells to recruit other immune cells or stimulate effector cells.[10]

Most cancer neoantigens in humans arise from unique mutations. A patient's cancer is intra- as well as interlesionally heterogeneous and changes its composition over time.[11] Each patient has an individual mutational signature (mutanome), and only a very small portion of the mutations are shared between patients.[10][12] A concept is therefore that an immunotherapy directed at neoantigens needs to be individualized.

The development of sequencing technology has improved the accuracy of identification and localization of neoantigens. With the advent of next-generation sequencing (NGS), it has become possible to systematically predict cancer neoantigens for individual patients.[5][13]

In animal models, several independent studies have shown that vaccines consisting of computationally predicted neoepitopes mediated anti-tumor activity in mice.[13][14][15][16][17]

The translation of individualized neoepitope vaccines into clinical oncology is under investigation. Formats under consideration for individualized vaccines are synthetic peptides, messenger RNA, DNA plasmids, viral vectors, engineered bacteria, and antigen-loaded dendritic cells.[2]

Individualized cancer vaccines typically consist of multiple predicted neoepitopes. The manufacturing process involves several steps.

Tumor biopsies and healthy tissue (e.g., peripheral blood cells) of a patient diagnosed with cancer are examined by NGS. Tumor-specific mutations in protein-coding genes are then identified by comparison of sequences from tumor and normal DNA. Computational tools classify these mutations for the highest likelihood of immunogenicity, that is, for the predicted expression and binding affinity of neoepitopes on HLA molecules. The top rankers are then used for the production of the vaccine.[4]

The intended output is an on-demand vaccine with a unique composition tailored to the patient's individual cancer mutanome.[10]

The research approach to mobilize an immune response tailored to the individual tumor of a patient is also referred to as individualized neoantigen-specific immunotherapy (iNeST).

iNeST is based on the specific tumor mutations (neoantigens) of a single patient, with the aim of triggering high-affinity immune responses of T cells to the individual patient-specific cancer.[19] The development of iNeST is driven by biotech companies[23][24]