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NEOANTIGEN VACCINES
Introduction
We now turn to neoantigen-based cancer vaccines. The objective of a vaccine is to introduce a small amount
[77]
of material to instruct T and B cells to eliminate invaders that present the cognate antigen . Vaccines in
general can be prophylactic (preventative) or therapeutic (cure or control of observable disease). Current
neoantigen vaccines are therapeutic, with the goal of restoring immune surveillance of a tumor that has likely
already evolved to evade the immune system (e.g. through immunoediting; see below).

Cancer cells are genomically unstable [41,78] , which leads to the expression of novel proteins due to non-
synonymous mutations. Many of these are likely to be immunogenic and are termed neoantigens. Vaccines
that precisely target such neoantigens (also known as tumor-specific antigens, or TSAs) would prime an
immune response that rejects tumors while sparing normal tissues, leading to optimal therapies with mild if
[79]
any toxicity. A timeline that traces the foundations of this idea back to 1943 is provided by Coulie et al. .

Types of antigen-based cancer vaccines
Prior to the advent of next-generation sequencing, cancer vaccines were developed based on TAAs or cancer
germline antigens. These self-antigens are overexpressed in tumors, or normally expressed only during
development but re-expressed in tumors. Vaccines targeting these can be produced in advance at lower cost
and applied across a range of tumors that share expression of the target. As the targets are self-antigens, such
vaccines are possibly limited by self-tolerance and adverse events. Tumor resistance mechanisms, many of
which are shared with neoantigen vaccines, are also a prominent concern [80,81] . Another class of targets are
shared tumor neoantigens, which are commonly found across a subtype of tumor. As in TAAs, the vaccine
can be produced beforehand, and treatment progress can be easily followed, as the neoantigen epitopes
(i.e. recognized peptide fragments) are typically well known. Such epitopes however may not be the most
effective for any given tumor.

With massively parallel sequencing and MHC binding and functional prediction software tools, the key
hurdle to developing personalized neoantigen vaccines can now be overcome. Vaccines custom designed for
[82]
each patient represents a paradigm shift in cancer treatment .

Some of the strengths and weaknesses of the neoantigen vaccine approach are summarized in Table 1 and are
discussed further below.

Vaccine formulation and administration
In addition to the selection of epitopes, a number of other considerations can strongly influence the success
or failure of neoantigen vaccines. Cancer vaccines can be formulated as whole cells, peptides/proteins, RNA,
[83]
[80]
DNA , and glycolipids . Vaccines are typically formulated as peptides, due to ease of construction and
low cost, although these are often observed to be weakly immunogenic. They can be modified to enhance
[84]
delivery to immune cells and improve pMHC binding stability . Synthetic long peptides require dendritic
[85]
cell processing, argued as essential for durable response . Protein vaccines are more immunogenic but
have a higher risk of anaphylaxis. The robust discussion about designing and assessing peptide vaccines has
[86]
been reviewed by Kumai et al. . DNA vaccines introduce DNA coding for antigenic fragments into host
cells, where they are expressed and lead to the presentation of epitopes via the MHC-I pathway. They are
generally safe, stable, and easy to produce at low cost, although currently weakly immunogenic. The vaccine
[87]
or delivery vehicle itself can be attacked by the host immune system . RNA vaccines can encode several
epitopes on a single molecule, can trigger the innate immune system, and are not at risk of integrating
into the genome [88-90] . Whole cell vaccines that employ weakened or killed tumor cells can trigger immune
response with the entire complement of tumor antigens, without specific instruction of the immune system,
reducing time and expense. They may however induce immune response to self-proteins.