Page 277 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

256 PART III Therapeutic Modalities for the Cancer Patient

Utilizing Stem Cells to Deliver “Suicide Genes” ability of an activated CD8+ T cell. 50–52 A similar approach has
been employed in dogs, creating CD20-directed CAR T-cells
that demonstrated feasibility, if with only modest clinical
The attractiveness of enzyme–prodrug cancer gene therapy has
VetBooks.ir been described earlier, but it relies on the ability to specifically responses.
53
target prodrugs to tumors. Prodrug cancer gene therapy driven
by MSCs has been suggested as a treatment modality that could Gene Modification to Improve Chemotherapy
achieve this. 39–42 Thanks to their immunosuppressive proper- and/or Radiation Therapy Outcomes
ties, allogeneic MSCs can substitute for autologous stem cells in
delivering the therapeutic agent in targeted tumor therapy, and An alternative approach to gene therapy for cancer involves the
the tumor-homing ability of MSCs holds therapeutic advantages delivery of genes to normal cells of the bone marrow to protect
compared with vehicles such as proteins, antibodies, nanoparti- them against the cytotoxic effects of conventional chemothera-
cles, and to some extent viruses. peutic drugs. In particular, the multidrug resistance (MDR) gene
has been cloned and delivered to normal bone marrow cells.
Gene-Directed Immunotherapy When patients are given high doses of chemotherapy, the normal
cells with the MDR gene are able to export the toxic drugs across
The search for an effective cancer vaccine over the past 150 years has their membranes, reducing potential side effects. 54–56 However,
led to extensive studies of the immune response of cancer patients. this approach does not protect gastrointestinal cells, which limits
These studies have suggested that cell-mediated immune responses its usefulness. Furthermore, there is also a danger that the MDR
are important components of the antitumor immune response. gene could transfer to malignant cells, rendering them insensitive
Cytokines are small glycoprotein molecules that orchestrate the to the effects of standard drugs.
immune response, tissue repair, and hematopoiesis, and it has been An alternative approach is to enhance the sensitivity of cancer
demonstrated that the relative amounts of individual cytokines cells to either chemotherapy or radiation therapy (RT) to improve
can direct the immune system toward either a mainly humoral or clinical outcomes. As an example, the transcription factor Slug
a mainly cell-mediated response. In particular, cytokines such as has been identified as a potential mediator of radio-resistance and
interleukin-2 (IL-2), interferon-gamma (IFN-γ), IL-12, and IL-18 has been found to have an antiapoptotic effect. A recent study
have the ability to promote cell-mediated responses. Furthermore, demonstrated that the modulation of Slug expression by siRNA
evidence derived from animal models suggested that local produc- affected oral squamous cell carcinoma sensitivity to RT through
57
tion of cytokines around a tumor mass can lead to production upregulating p53 upregulated modulator of apoptosis (PUMA).
of an antitumor immune response and a reversal of T-cell anergy Furthermore, inhibition of the Notch and epidermal growth fac-
(nonresponsiveness). 43,44 Thus there appears a rationale for using tor receptor (EGFR) pathways in cancer have been shown to mod-
cytokine molecules in cancer patients to improve the antitumor ulate chemotherapy and radiosensitivity, opening the possibility
immune response to tumors that present weakly antigenic epit- of gene modulation during treatment with standard conventional
opes or epitopes that evade immune recognition. In the 1980s and modalities. 58,59 The limitation, as with all other gene therapy
1990s, a number of clinical studies were undertaken using recom- approaches, is in the capacity for efficient gene delivery.
binant cytokine proteins to improve the survival of human cancer
patients. However, cytokines tend to be autocrine or paracrine in The Use of Replication-Competent Viral Vectors
nature and the levels of protein required to demonstrate a biologic
effect were often too toxic for the patient to withstand. However, Progress has been made in the development of replication-com-
a more promising approach has been to deliver the actual cytokine petent viruses that conditionally replicate in cancer cells. 60–63 As
genes to cancer cells rather than delivery of the protein to the an example, the ONYX-015 vector (as described earlier) was one
whole patient. 45–47 Many trials have now combined this approach of the earliest vectors to enter into clinical trials. Since that time,
with gene-directed immunotherapy. In this approach, cytokine oncolytic viruses (OVs) have been emerging as important thera-
genes, and the prodrug-activating gene, are delivered to cancer peutics in cancer management, combining both tumor-specific
cells. The conversion of an inactive prodrug by the activating gene cell killing, together with stimulation of host immunity. OVs
64
leads to destruction of the cancer cells by necrosis. The codelivery represent a diverse group of agents that cause lysis during their
of cytokines that enhance cell-mediated immune responses such natural life cycle (e.g., vaccinia) or can be engineered to be lytic by
as IL-2, IFN-γ, IL-12, and IL-18 enhances the antitumor response toxic transgene expression. OVs can cause selective tumor cell kill-
and may potentially improve the distant bystander effect against ing by virtue of virus-specific receptors on the surface of the cancer
micrometastatic disease. This approach has also been adopted cell and/or by the tumor cell replicative machinery. In addition,
1
in a number of small-scale veterinary studies, including one on tumor lysis can lead to the promotion of antitumor immunity.
canine malignant melanoma, which used cells to deliver IL-2 to There are some wild-type viruses that are in clinical use (e.g., reo-
tumors. 48,49 These studies have had encouraging results and war- viruses, vaccinia virus and Newcastle disease virus), but many are
rant further larger scale trials. attenuated and/or engineered to improve selectivity or mode of
More recently, cancer immunotherapy based on the genetic action (e.g., E1b-deleted Ad5). 64,65
modification of autologous T cells has gained a great deal of The effectiveness of OVs has been demonstrated in preclinical
attention for successes in the treatment of leukemias and lym- models and has led to the FDA approval and conditional Euro-
phomas resistant to standard therapies. 50,51 In this, autologous pean Medicine Agency’s approval of the first OV for use in human
CD8+ T cells are engineered to recognize and kill tumor cells melanoma, the immunostimulatory herpesvirus, talimogene laher-
bearing specific surface antigens. This is achieved through cel- parepvec. In this, the Herpes simplex virus has been engineered
lular modification by the incorporation of a chimeric antigen such that both copies of the viral gene coding for ICP34.5 have
receptor (CAR) to redirected T cells, and combines the specific- been deleted and replaced with the gene coding for human granu-
ity of a monoclonal antibody with the proliferative and cytotoxic locyte-macrophage colony-stimulating factor (GM-CSF), and the