IMMUNE MANIPULATION IN CANCER TREATMENT: FROM WISHFUL
THINKING TO TUMORS SHRINKING
Holy Grail of cancer therapy has been to cause tumors in patients to
minimal adverse effects on normal tissues. It has been clear, in concept,
that one way to achieve this end would be to use the specificity implicit
in the human immune system to recognize and destroy cancer cells while
sparing normal cells.
Over the last 40 years there have been many attempts to stimulate the
immune system in cancer patients in the hope that the this nonspecific
stimulation would cause the immune system to recognize and destroy cancer
cells. The literature is peppered with trials using non-specific immune
stimulating adjuvants like BCG (Bacillus Calmette Guerin). Although some
studies suggested some traces of antitumor activity, the overall assessment
Dramatic and clinically meaningful responses didn't occur.
Other approaches to stimulate immunity by infusing patients with cells
thought to have antitumor activity using auto and allogeneic stem cell
transfer were both toxic and clinically disappointing. The adoptive
transfer lymphoid cells, which had been "educated" in vitro to recognize
and destroy patient's cancers (IL2/LAK and TIL infusions) tended to be very
toxic. Although significant responses occurred, they were rare and
were obtained with toxic side effects that were frequently very severe.
there have been examples of more significant, more specific and more
sophisticated immune manipulation that may be the leading edge of immune
therapies that will be widely applicable to patients with cancer.
What may be a "breakthrough strategy" of immune manipulation in cancer has been
demonstrated in melanoma. The FDA recently approved the monoclonal antibody
Ipilimumab for use in patients with metastatic melanoma. This therapy is
unique because its mechanism of action is to increase T-cell antitumor
activity by blocking factors suppressing T-cell antitumor activity. Thus
the intrinsic antitumor immunity in patients is allowed to function and
results in meaningful clinical results (improved survival). Ipilimumab has
the capability of producing autoimmunity since it blocks suppression of
immune activity. However, clinical toxicity seems manageable.
Other types of cancer may benefit from Ipilimumab or therapies with a
similar mechanism of action.
second example of a very intriguing immune manipulation in cancer has been
reported this week from Rosenberg and colleagues work at the NCI.
This group has been studying Adoptive Cell Transfer (ACT) in patients with
metastatic cancer for the last 35 years. ACT, although frequently very
toxic especially when given with high dose interleukin-2 (IL2),
occasionally resulted in tumor regression. Rosenberg's group now report
results in a patient with metastatic bile duct carcinoma who had had very
meaningful tumor responses to ACT using a subset of TIL (Tumor Infiltrating
Lymphocytes) selected to be cytotoxic to cancer cells carrying a mutation,
ERBB2, of an ERBB2 interacting protein. Toxicity of ACT in this setting is
manageable and the patient's performance status after therapy is excellent.
be excited about Ipilimumab and the admittedly, very early results of the
newest iteration of ACT from the NCI group? First,
the use of immunotherapy may be able to circumvent inherent chemotherapy
resistance. Secondly one can imagine that ACT with specific
tumorcidal T-cells might combine very nicely with Ipilimumab like agents
which enhance T-cell mediated tumor cell death. Further evaluation of
this strategy may warrant further testing.
indeed, we are leaving the age of wishful thinking and are closing in on a
new age of tumor shrinkage in the immune therapy of cancer.
Colin D. Weekes,
Research PI for The Academic GI Cancer Consultant
Consortium (AGICC) of The Oncology Consortia of CRITERIUM, INC. Global CRO
Dr. Colin D. Weekes is Assistant Professor, Division of
Medical Oncology at UCCC. He initially trained at the University of
Nebraska Medical Center where he completed a combined M.D., Ph.D
program. His graduate training was in cell biology and focused on
lymphoma cell chemotherapy resistance. Following completion of
medical school, he matriculated through a internal medicine residency at
the University of Alabama Birmingham. Dr. Weekes focused on the
translational research in the development of novel therapies for pancreatic
cancer during my medical oncology fellowship at Johns Hopkins Hospital.
Dr. Weekes has an
active clinic focused on the management of all gastrointestinal
malignancies and early phase clinical studies as part of the developmental
therapeutics clinic. In addition, he directs a translational research
laboratory focused on developing therapies targeting the tumor
microenvironment for the treatment GI malignancies. Dr Weekes is an
active member of the American Society of Clinical Oncology (ASCO), American
Association for Cancer Research (AACR) as well as the Pancreatic Cancer
Click HERE to see more about Dr. Weekes at the University of