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two fronts: complete durable patient response was achieved in a substantial fraction of patients in the clinic,
and the mechanism of action was T-cell antigen-specific. This spurred confidence that therapy approaching
a “cure” was at hand, based on a rational extrapolation of current knowledge. The immune system is
inextricably linked to both the phenomenon of cancer and its treatment. This represents a paradigm shift,
where cancer is no longer seen as just a collection of aberrant cells, but rather a systemic disease.

While this new vista continues to capture the public imagination worldwide, we have learned enough
over the years to understand that cancer immunotherapy, in its current form, is not a panacea. The central
challenge facing cancer immunotherapies and neoantigen vaccines in particular is understanding resistance.

Integrating immunology and cancer research, already two of the most complex topics in biomedicine, is an
interdisciplinary effort, drawing from fields such as biology, pharmacology, chemistry, physics, engineering,
statistics, and mathematics. Our main aim in this primer is to lower the barrier to entry for readers who are
not specialists in immunotherapy. We focus on neoantigen vaccines, which in some ways represent T-cell
based cancer immunotherapy in its most elementary form. We also address general issues, enabling readers
to quickly grasp other immunotherapies and future developments.

Background on the immune system and cancer
We embark first on a brief tour of immunology, with the caveat that the specifics and even the broad outlines
may shift as the field advances. Many of the features described below have bearing on possible cancer
resistance mechanisms.

In brief, the requirements for an effective immune system include mechanisms to recognize foreign invaders,
the means to trigger and coordinate a potentially complex attack (“expansion”), then return to equilibrium
(“contraction”), while not attacking normal tissue. This rests critically on the ability to distinguish self from
non-self. In vertebrates, robust response also leads to the development of immune memory. Immunotherapy
can be viewed as an attempt to shift the equilibrium point in a complex system that can actively amplify or
suppress its effects.

Cancer cells can evade the immune system through a variety of routes, such as being viewed as self, hijacking
suppressive mechanisms that prevent damage, attacking or subverting immune system agents, or simply
growing at a rate beyond the capacity of an often aged and weakened immune system.

[3]
The vertebrate immune system is broadly divided into two arms. Innate immunity is encoded in the
[4]
germline, while adaptive (“acquired”) immunity is mediated by B and T lymphocytes that undergo
processes of diversification and selection. T cell selection relies on processes of central tolerance (at the
[5]
thymus) and peripheral tolerance (on mature circulating T cells) . The two arms interact, with some cell
types having a role in both arms.

In the adaptive system, T cells play the key role in recognizing pathology via antigens. The core of this task
involves three parts: a presenter (major histocompatibility complex molecule, MHC), an antigen fragment
(peptide), and a recognizer (T cell receptor, TCR). Elaborate processes of MHC expression and maturation,
antigen processing, peptide MHC loading, and generation of mature naive T cells through the thymus
[6-9]
underlie their formation and interaction .
Antigen recognition takes place when a receptor on a T cell encounters a cell presenting a cognate peptide-
MHC (pMHC) complex on its surface. If a CD28 co-stimulatory receptor on the T cell simultaneously binds
with CD80 or CD86 expressed on the presenting cell, an activation signal is propagated on the cytosolic side
of the TCR, leading to cell proliferation, differentiation, and secretion of cytokines. A lack of a co-stimulatory
[10]
signal leads to a hypo-responsive state known as T cell anergy . Inhibitory checkpoint molecules “put the