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Oiseth et al. Cancer immunotherapy

cancers and their metastatic derivatives are able to the first one to be used in cancer therapy, for treatment
generate an immunosuppressive, protumorogenic, of bladder carcinoma [45] , where it indirectly increases
and prometastatic microenvironment by recruiting the expression of tumor antigens after the tumor cells
and “training” immune cells, including macrophages, internalize the bacteria. This induces an intense and
regulatory T-cells, immature myeloid cells (which complex coordinated release of multiple cytokines,
become “myeloid-derived suppressor cells”), T helper including those from T helper 1 cells (IL-2, IL-12, IFN-γ,
17 cells, regulatory B cells, and leukocytes [38] . Even tumor necrosis factor), as well as those from T helper
before they metastasize, tumors can influence the 2 cells (IL-4, IL-5, IL-6, IL-10). Macrophages, epithelial
systemic environment by altering hematopoiesis as well cells, and fibroblasts contribute IL-8, and T helper 17
as the tissue parenchyma of organs at distant sites, cells release IL-17 [46] . This wide array of cytokines
thereby forming “pre-metastatic niches” [39] . While some then induces antitumor activity mediated by cytotoxic
cancer immunotherapies have had marked successes T lymphocytes, natural killer cells, neutrophils, and
in manipulating these tumor microenvironments, the macrophages.
loss of MHC class I expression by a tumor represents a
major immunotherapy treatment challenge [40] . ONCOLYTIC VIRUSES

The intrinsic immunological ability of an individual Oncolytic viruses are an emerging class of cancer
to combat cancer has been called the “cancer– therapeutics which lie at the junction of biologic therapy
immune set point”, and is influenced by a complex and immunotherapy. These viruses are genetically
set of factors involving the tumor, the host, and modified to lack virulence against normal cells but are
environmental factors [41] . Clinical studies are trying able to invade and lyse cancer cells which have sacrificed
to better characterize these factors to help predict a many of their normal anti-viral cellular defenses in order
person’s response to immunotherapy, as discussed in to amplify their growth potential. Lysis is only one of
the following paragraphs. multiple mechanisms involved in the viral-induced
destruction of cancer cells, which undergo further attack
BIOLOGIC MODIFIERS: CYTOKINES AND by an immune system stimulated by a plethora of tumor
VACCINES antigens released by lytic destruction [47] . The oncolytic
virus which was approved by the FDA in 2015 to treat
The term “immunotherapy” encompasses a wide variety advanced melanoma is a herpes simplex-1 virus (HSV-
of concepts and methods. Older and non-specific 1) named “T-VEC”, modified to express GM-CSF which
immunotherapies include immunostimulatory cytokines further stimulates proliferation of immune cells. T-VEC is
such as interleukin-2 (IL-2) and interferon (IFN). L-MTP injected directly into areas of melanoma that a surgeon
is a synthetic analogue of a bacterial cell wall that is cannot remove. Clinical trials are underway with other
capable of activating monocytes and macrophages oncolytic viruses for treatment of different types of
and has had limited success in cancer treatment as cancer, with some of these trials combined with other
reported in other countries; it is not approved by the types of cancer therapies.
Food and Drug Administration (FDA) of the USA [42] . The
only vaccine for cancer which has received approval by ADOPTIVE CELL THERAPY
the FDA is sipuleucel-T for metastatic castrate-resistant
prostate carcinoma. Dendritic cells from the patient are Adoptive cell therapy (ACT) is another type of
exposed to prostatic acid phosphatase and granulocyte- immunotherapy which mostly involves the isolation and
macrophage colony-stimulating factor (GM-CSF) in-vitro expansion of tumor-specific T-cells, followed
and reinfused into the patient. Treatment results in a by infusion back into the cancer patient. These efforts
4-month increase in median survival [43] . Sipuleucel-T is have also extended to using natural killer cells, since
a dendritic cell vaccine, while other types of vaccines they display rapid and potent immunity to solid tumor
employ killed tumor cells or selected tumor antigens, metastasis and hematological cancers [48] .
and various vaccines may use microorganisms as
vectors for delivery. Vaccine trials using multiple There are many forms of ACT, including those
neoantigens specific to an individual patient’s tumor using techniques such as culturing tumor-infiltrating
have shown promise in two small early trials [44] . The lymphocytes obtained directly from the tumor; isolating
goal of all of these tumor vaccines is try to expose and expanding one particular T-cell or clone; or using
patients to those tumor antigens which can provoke T-cells that have been engineered in vitro to potently
an antitumor immune response via the generation of recognize and attack tumors, which technique is known
tumor specific antibodies and/or T-cells. Vaccines are as chimeric antigen receptor T-cell (CAR T-cell) therapy.
one type of biologic response modifier, and BCG was The revolutionary CRISPR/Cas9 (or “CRISPR” for
254 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ October 31, 2017