Page 1068 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Immunotherapy of Cancer

Anu Sharma, Matthew Campbell, Cassian Yee, Sangeeta Goswami,
Padmanee Sharma

The ability of the immune system to recognize and eradicate KEY CONCEPTS
cancer was first postulated in the 19th century; however, proof
of principle remained elusive until later. It was noted that some Three Phases of Immune Interaction With
patients with sarcoma underwent spontaneous regression of their Tumor Cells
tumors upon incidental development of a skin infection with • Elimination: Tumor cells are detected and destroyed by the immune
Streptococcus pyogenes, which was conjectured to elicit an immune system.
response against the infection as well as against cancer cells. • Equilibrium: Tumor cells are not eliminated by the immune system.
After this observation, a mixture of heat-killed S. pyogenes and • Escape: Tumor cells escape immune control.
Serratia marcescens (Coley’s toxin) was used to treat patients
with sarcoma, which resulted in complete tumor regression in
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some patients. These early studies with Coley’s toxin prompted
many clinical trials aimed at stimulating the immune response The continuous interaction of cancer cells with the immune
to eradicate cancer, including the use of Bacille Calmette-Guérin system may favor the outgrowth of less immunogenic tumors that
2
(BCG) as a treatment for superficial bladder cancer. However, can escape immune control, termed the escape phase. Tumor cell
incomplete understanding of the mechanistic details of immune escape can occur through different mechanisms including (i) loss
responses led to failure of many early clinical trials. With recent of antigens and/or MHC expression; (ii) increased resistance to the
advances in our understanding of basic principles that guide cytotoxic effects of immunity through induction of antiapoptotic
immune responses, specifically T-cell responses, immunotherapy mechanisms; (iii) development of defects in antigen processing/
is now established as one of the pillars of cancer treatment. presentation; (iv) loss of crucial genes, such as genes related to the
One important principle that has reshaped our thinking of interferon (IFN) signaling pathway, which makes tumor cells more
cancer immunology is related to immunosurveillance. Cancer resistant to immune-mediated killing by IFN; or (v) recruitment
immunosurveillance relies on immune cells, including T cells, of immunosuppressive cells to the tumor microenvironment,
which can recognize antigens, including mutated proteins that which can inhibit antitumor immune responses and contribute
generate novel antigens. T cells recognize these antigens when to the escape of edited tumor variants. 5
they are bound to self-MHC (major histocompatibility complex)
molecules.
In the early 2000s, the hypothesis of cancer immunosurveil- KEY CONCEPTS
lance was redefined to state that the immune system controls Mechanisms of Tumor Cell Immune Escape
both the tumor quality (immunogenicity) and the quantity
(tumor load), thus eliminating tumors and sculpting the immu- • Loss of antigen or major histocompatibility complex (MHC)
expression
nogenic phenotypes of tumors in immunocompetent hosts. The • Resistance to cytotoxicity
interaction between the host immune system and the tumor • Defects in tumor antigen processing/presentation
cells has been proposed in three phases, including elimination, • Loss of crucial genes involved in the immune response
equilibrium, and escape (the three E’s). In the elimination phase, • Recruitment of immunosuppressive cells to the tumor microenviron-
cancer cells are detected and destroyed by the adaptive and innate ment
arms of the immune system before becoming clinically apparent.
These data helped to frame the importance of the immune system
in cancer development and revived the theory of cancer Besides increasing our understanding of immunosurveillance,
immunosurveillance. 3 we have gained new insights regarding mechanisms that regulate
Cancer cells that evade elimination enter the equilibrium T-cell responses, which have led to the development of an entirely
phase, where T cells keep the remaining cancer cells in check new field known as immune checkpoint therapy. The current
without eliminating them. This phase may extend throughout chapter will discuss (i) Activation and regulation of T-cell
3
the host’s lifetime. Clinical examples of the equilibrium phase responses, (ii) Immune checkpoint therapy, (iii) Other inhibitory
include the duration between successful treatment of the primary immune checkpoints, (iv) Immune checkpoint therapy
tumor and relapse, the existence of disease-free state despite with clinical benefits in solid tumors and hematological malignan-
micrometastasis, and the development of donor-derived tumors cies, (v) Early and late-phase trials with immune checkpoint
after organ transplant. 4 therapy in other tumors, (vi) Immune costimulatory molecules,

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