Biological Response Modifiers in Human Oncology and Immunology
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They were able to clone the melanoma antigen-encoding gene MAGE , which encodes an antigen recognized by cytotoxic T-cells. This provided not only proof that the immune system was capable of seeking and destroying tumor cells but also provided the first identification of a molecular target. The ability of cancer cells to evade immune destruction has been proposed as the eighth hallmark of cancer [ 37 ]. While some cancer immunotherapies have had marked successes in manipulating these tumor microenvironments, the loss of MHC class I expression by a tumor represents a major immunotherapy treatment challenge [ 40 ].
Older and non-specific immunotherapies include immunostimulatory cytokines such as interleukin-2 IL-2 and interferon IFN. L-MTP is a synthetic analogue of a bacterial cell wall that is capable of activating monocytes and macrophages and has had limited success in cancer treatment as reported in other countries; it is not approved by the Food and Drug Administration FDA of the USA [ 42 ].
The only vaccine for cancer which has received approval by the FDA is sipuleucel-T for metastatic castrate-resistant prostate carcinoma. Dendritic cells from the patient are exposed to prostatic acid phosphatase and granulocyte-macrophage colony-stimulating factor GM-CSF and reinfused into the patient.
Treatment results in a 4-month increase in median survival [ 43 ]. Sipuleucel-T is a dendritic cell vaccine, while other types of vaccines employ killed tumor cells or selected tumor antigens, and various vaccines may use microorganisms as vectors for delivery. Vaccines are one type of biologic response modifier, and BCG was the first one to be used in cancer therapy, for treatment of bladder carcinoma [ 45 ] , where it indirectly increases the expression of tumor antigens after the tumor cells internalize the bacteria.
Macrophages, epithelial cells, and fibroblasts contribute IL-8, and T helper 17 cells release IL [ 46 ]. This wide array of cytokines then induces antitumor activity mediated by cytotoxic T lymphocytes, natural killer cells, neutrophils, and macrophages. Oncolytic viruses are an emerging class of cancer therapeutics which lie at the junction of biologic therapy and immunotherapy.
These viruses are genetically modified to lack virulence against normal cells but are able to invade and lyse cancer cells which have sacrificed many of their normal anti-viral cellular defenses in order to amplify their growth potential. Lysis is only one of multiple mechanisms involved in the viral-induced destruction of cancer cells, which undergo further attack by an immune system stimulated by a plethora of tumor antigens released by lytic destruction [ 47 ].
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T-VEC is injected directly into areas of melanoma that a surgeon cannot remove. Clinical trials are underway with other oncolytic viruses for treatment of different types of cancer, with some of these trials combined with other types of cancer therapies.
Adoptive cell therapy ACT is another type of immunotherapy which mostly involves the isolation and in-vitro expansion of tumor-specific T-cells, followed by infusion back into the cancer patient. These efforts have also extended to using natural killer cells, since they display rapid and potent immunity to solid tumor metastasis and hematological cancers [ 48 ].
Biological Response Modifiers in Human Oncology and Immunology
There are many forms of ACT, including those using techniques such as culturing tumor-infiltrating lymphocytes obtained directly from the tumor; isolating and expanding one particular T-cell or clone; or using T-cells that have been engineered in vitro to potently recognize and attack tumors, which technique is known as chimeric antigen receptor T-cell CAR T-cell therapy. In , the method was adapted for use in eukaryotic cells [ 50 ] , and in late a group at Szechuan University became the first to use CRISPR-edited cells in humans [ 51 ].
Other similar trials are scheduled to start in in the United States. Researchers are still studying other ways of modifying T-cells to treat cancer. Relapsed and refractory B-cell acute lymphoblastic leukemia in pediatric and young adult patients is the first disease to receive approval from the FDA for CAR T-cell therapy, outside of clinical trials [ 54 ]. Although it is a mostly reversible physiologic protective mechanism against autoimmunity, the first observation of it was made in mice infected with a chronically persistent strain of lymphocytic choriomeningitis virus [ 55 ].
This T-cell dysfunction was later discovered to exist in multiple other conditions involving persistent antigen exposure by other viruses such as HIV, hepatitis B, and hepatitis C, or by cancer, thereby allowing these agents to avoid detection and destruction by immune cells [ 35 , 56 - 59 ].
Some of these molecules are similar to more common or better-known membrane moieties but with important differences: for example, lymphocyte-activated gene-3 LAG-3 is structurally homologous to CD4 but has a higher binding affinity to MHC class II antigens than CD4. Unlike CTLA-4, PD-1 does not interfere with costimulation, but generates signals that prevent phosphorylation of key signaling intermediates in the T-cell, which reduces their activation [ 67 ]. While B7 ligands are expressed by professional APCs includes dendritic cells, macrophages and B cells , PD-L1 can be expressed on many cell types, including T-cells, epithelial cells, endothelial cells, and tumor cells after exposure to interferon-gamma, produced later in the immune response by activated T cells.
PD-L2 is primarily expressed on dendritic cells and monocytes, but can be induced in a wide variety of other immune cells and nonimmune cells [ 68 ]. They are receiving much attention recently because they are much less toxic than conventional cancer therapies, are easier to prepare and administer than other types of cancer immunotherapeutics, and have great potential for widespread application.
Assays of PD-L1 protein expression by immunohistochemistry are used to determine which tumors would best be treated with an anti-PD-L1 antibody, but it is an imperfect measurement practice because there is lack of standardization of methods and it can sometimes be difficult to differentiate PD-L1-positive tumor cells from the other PD-L1-positive cells in the tumor microenvironment [ 73 ].
The wide ranges in the percentages of adverse effects reported reflect the variabilities associated with single or multiple drug regimens, dosage levels, and types of malignancies treated. Corticosteroids or other immunomodulators can reverse nearly all of the toxic manifestations of these drugs [ 75 - 78 ]. Pneumonitis is an uncommon but potentially severe complication, and rarely deaths have occurred [ 80 ].
These drugs have powerful effects, as seen when a Phase I trial using an antibody to the CD28 ligand nearly cost the lives of all six healthy volunteers in a British study when a cytokine storm was provoked, associated with multiorgan failure and resuscitation in the intensive care unit [ 81 ]. Since this reaction occurred after the very first infusion of a dose times smaller than that found safe in animal studies, this study raised awareness of the need to develop better animal models which more closely mimic drug behavior in humans.
Glucans and Cancer: Historical Perspective Sima P, Vannucci L, Vetvicka V - Cancer Transl Med
In addition, there was increased appreciation of the wisdom of restricting the initial testing of a new pharmaceutical to only a few human subjects [ 82 ]. Some of these trials are using specific antibodies to modulate the function of the more recently discovered inhibitory and co-stimulatory checkpoint molecules. These are necessary in order to generate hypotheses that can then be tested in animal models and thereby provide more precise biologic pathways about tumor immunity and rejection [ 85 ].
Lung cancers occurring in smokers have a higher mutational burden and have shown more responsiveness to ICIs [ 89 ]. Another study of patients with metastatic renal cell carcinoma showed faster tumor progression in the patients who had received broad-spectrum antibiotics up to one month before treatment with ICIs [ 93 ]. Not all immune checkpoint or immunomodulatory molecules take the form of a receptor or ligand.
Some may be expressed by the cell in a free soluble form, such as indoleamine 2,3-dioxygenase IDO1 , an enzyme produced by some activated macrophages and also overexpressed by many tumors [ 94 ]. The enzyme depletes tryptophan in the microenvironment, with production of the catabolite kynurenine, which harms the cytotoxic T-cells. Since the immune system has the capacity to remember and the ability to detect and destroy tumor variants as they emerge, immunotherapy will always possess inherent advantages over other therapies that lack these two key attributes.
The challenges ahead are to discover why immunotherapy treatments work so dramatically well in some cancers and in some patients while not at all in others, and how tumors which were once sensitive to treatment can acquire resistance. One recent study with large therapeutic and prognostic implications used the new CRISPR technique to reveal multiple mutations in the tumor genes of individual patients who failed immunotherapy [ 96 ].
Some of these identified genes may be associated with loss of tumor antigen expression, while others may involve disturbances in tumor cytokine production or T-cell co-stimulation. The pharmacoeconomics of these treatments also needs to be considered. Immunotherapy drugs are now approved for treatment of multiple cancer types either as first-line treatment or when standard first-line treatment has failed. The FDA has recently approved the anti-PD-1 antibody pembrolizumab for the treatment of any unresectable or microsatellite instability-high or mismatch repair-deficient solid tumors that have progressed after prior treatment and who have no other satisfactory treatment options [ 99 ].
This is the first time the agency has approved a cancer treatment based on a common biomarker rather than the location of the body where the tumor originated. Immunotherapies do not yet represent a panacea in cancer therapy since only a minor subset of some cancers respond to some of these treatments, and it is difficult or impossible to determine precisely who will benefit.
Before finishing this brief review, it is proper to recognize the work of Dr. Gay P, Prasad V.
Biological response modifier
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