Page 263 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

242 PART III Therapeutic Modalities for the Cancer Patient

of CD4+ T cells for ACT, rather than cytotoxic CD8+ T cells, as Natural Killer Cell Immunotherapy
CD4+ T cells are capable of activating both innate immune cells Lastly, there is a growing interest in using NK cells for immuno-
However, CD4+ T cells contain Treg
237,238
and CD8+ T cells.
VetBooks.ir cells; thus strategies to block the development of Treg cells dur- therapy. A recent canine immunotherapy review states that the
237
ing CD4+ T cell ACT have been investigated.
author’s institution is currently conducting a phase II canine clini-
In addition, the
availability of TAs appears to also play a role in the strength of cal trial using autologouse NK cells that were activated ex vivo for
CD4+ ACT therapy. 239 Similarly, the addition of cytokines and/or treatment of appendicular OSA. 258
blocking antibodies against suppressor cells, along with ACTs, has
been shown to enhance the effectiveness of this therapy. 237,240–242 The Future of Cancer Immunotherapy
More recently, there has been interest in developing chimeric
antigen receptor (CAR) T cells for canine immunotherapy. CAR-T The use of immunotherapy for the treatment of cancer is an excit-
cells are generated via transfection of antibody genes specific for ing and ever-evolving field of research and application. With the
a tumor target into a T cell. 243–247 This directs the engineered T advancement of techniques used to assess immune responses to
cells specifically to the tumor tissue. Success with this technol- tumors, better ways of predicting responses, including develop-
ogy has been seen in humans with chronic lymphocytic leuke- ment of Response Evaluation Criteria in Solid Tumors (RECIST),
mia where the T cells target the CD19+ B cells. 244,245 In terms and an understanding that tumor responses to immunotherapies
of veterinary use, initial in vitro studies were performed looking may be delayed compared with conventional chemotherapy, radi-
at autologous T cells transfected with the HER2 gene to target ation therapy and surgery, one can more reliably assess the clinical
canine osteosarcoma cells. 248 More recently, Panjwani et al trans- efficacy and safety of novel immunotherapies. Moreover, a better
fected canine T cells with CD20-targeting RNA for dogs with B understanding of the disease pathology in our veterinary patients
cell lymphoma. 249 This was the first study to show that these cells has led to a movement toward using spontaneous canine and feline
could be made, expanded, and safely administered to dogs. cancers as models for human disease, thus allowing for testing of
novel immunotherapies in our small animal patients that will ben-
Transfer of Lymphokine-Activated Killer Cells efit not only them, but human cancer patients as well. 259,260
However, the development of a successful immunotherapy
Initial T-cell transfer studies involved the generation of lympho- protocol is not without limitations. One of the main reasons for
kine-activated killer (LAK) cells. This was done by culturing failure of many immunotherapies is due to the immunosuppres-
PBMCs in high concentrations of IL-2, thus selecting for a popu- sive microenvironment established by the tumor. Thus immuno-
lation of cells with potent tumor cell lysis ability. Clinical trials therapies that are best able to overcome this suppression will prove
using this technique in humans were disappointing and unfeasible the most successful. 261 In addition, the use of certain drugs and/or
despite promising mouse studies. 250 The use of LAK cells in vet- proteins that can deplete or inactivate the key players in immune
erinary medicine is limited to studies of cats with FeLV or FIV. 251 suppression, i.e., MDSCs and Tregs, and therapies that target
checkpoint molecules may be best used in concert with novel vac-
Transfer of Tumor-Infiltrating Lymphocytes cines or other immunotherapies to optimize their effectiveness.
Along those lines, the use of newer and more potent adjuvants,
One source of potent antitumor T cells is in the tumor itself. These such as various preparations of CpG motifs, to stimulate the
cells, called tumor-infiltrating lymphocytes (TILs), when expanded immune system will be a critical component of newer vaccines.
using IL-2, exhibit potent cytolytic activity that is many folds higher It has now become clear that the most successful adjuvants are
than LAK cells against tumors in both a specific and nonspecific ones that not only stimulate a strong primary response against
way. 252 Although they are considered the best source of T cells for the tumor, but ones that also lead to the development of a robust
ACT, 253,254 their use in human medicine is limited because of a central memory response.
few variables such as time of isolation, the tumor they were isolated One of the more successful categories of immunotherapies cur-
from, and the functional state of the cells when isolated. 250 None- rently used in human medicine is mAbs. Advances in technology
theless, limited success has been observed in cases of treating human led to the development of humanized, nonimmunogenic forms
melanoma with TILs, particularly when combined with non- of antibodies against key cellular receptors, either to activate key
myeloablative chemotherapy such as fludarabine and cyclophos- antitumor immune cells or lead to cytolytic activity against tumor
phamide, which deplete lymphocytes but spare bone marrow stem cells. However, similar advances in treating dogs with mAbs are
cells. 255 In one study, 6 of 13 melanoma patients had significant not currently available, although development of such reagents is
tumor regression and four had a mixed response including regres- underway by many investigators and companies.
sion of some lesions and growth of others. 255 In a follow-up study It should be understood that many, if not all, immunothera-
involving a larger number of patients (34 in total), tumor regres- pies developed should work in concert and synergize with cur-
sion was seen in 51% of the patients that received chemotherapy rent cancer treatment modalities. Given the ability of tumor
before the TIL transfer and IL-2 treatment. 256 In addition to the cells to become resistant to chemotherapy and radiation therapy
use of nonmyeloablative treatments, recent studies have investigated and their ability to suppress the immune system, one would
the use of other forms of Th1 stimulation along with ACT. One be naïve to think that a single-modality treatment is the most
group has investigated the use of adding CpG-ODNs to their TILs effective means of tumor control. Although the immune system
to increase their efficacy. 257 In a study using ex vivo isolated human can be manipulated to mount an effective antitumor immune
TILs, instillation of the activated TILs with CpG-ODN into athy- response, it is best used in cases of residual and metastatic dis-
mic nude, tumor-bearing mice, resulted in decreased tumor bur- ease, where radiation therapy, chemotherapy, and/or surgery are
den and prolonged survival. Regardless of the human clinical trials’ used to cytoreduce and down-stage large tumors. Moreover, it
results, the use of TILs in veterinary medicine is absent, perhaps is becoming very clear that the immune system is a key player
owing to the lack of reliable efficacy across multiple tumor types. involved in the tumor responses to radiation and chemotherapy,