- Prostate cancer is an immunologically cold cancer with hardly any
T-cell response within the tumor microenvironment.
- Prostate cancer is noted for its resistance to immunotherapy
- Current study suggests that using combination of agents in
immunotherapy might improve patient response, rather than using them
activity against tumor cells and therefore patient response could be improved
by using combination of agents, that are often ineffective when used alone,
according to a recent study by The University of Texas MD Anderson
Cancer Center led by Padmanee Sharma, M.D., Ph.D., professor of Genitourinary
Medical Oncology and Immunology.
team of scientists wished to assess if tumor infiltration by immunocompetent T-cells could
be enhanced in prostate cancer by combining Lupron, an anti-hormonal drug along with two
the negative immune checkpoint regulator (NCR) inhibitor ipilimumab
surgery, especially in patients
with locally advanced disease.
‘Employing checkpoint inhibitors such as ipilimumab and nivolumab together produce better responses than using singly, as they act at different points.’
and Findings of the Study
Seventeen patients participated in the Lupron-ipilimumab trial
; 16 completed
treatment followed surgery and one patient died of a cardiac complication
before surgery. The important findings included the following:
- Six patients displayed cancer
progression while 10 were without evidence of
- progression for at least 3.5 years
- All 16 patients were living 3.5
years after surgery
- All 17 showed an adverse immune
reaction, with 8 of them experiencing the most serious grade 3 or 4 side
effects, such as inflammation of the colon, pituitary gland or pancreas
and elevated liver enzymes signifying injury. All of them were
administered corticosteroids and other immune-suppressive agents.
Notable Observations From the Study
other important observations during the current study have led the authors to
believe that any immune response against
a tumor must be looked at in its entirety rather than one immune response at a
. This is especially important because the immune response is a dynamic
phenomenon and a single specific immune response may influence the subsequent
responses in unexpected ways as outlined below:
Following treatment with ipilimumab
cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor
- Immune T-cells come into the tumor milieu, but was followed by increased
expression of other negative
checkpoint regulators (NCRs) such as programmed death PD-1 and V-domain immunoglobulin
(Ig)-containing suppressor of T-cell activation (VISTA) on T-cells that render the T-cells ineffective.
- Expression of PD-1 and VISTA on macrophages ( a type of immune cells) were also increased, converting
them into a M2 mode which promotes tumor growth and spread.
The M1 mode is the one that stimulates immune response against the tumor.
concluded that driving T cells into the tumors would be step one
then the next step would be to block PD-L1 and VISTA
," Sharma said,
suggesting that a combination of immunotherapeutic agents acting at different
levels would have a better outcome.
These observations were made by analyzing
samples of tumor tissue taken during and after treatment.
"Understanding these changes using
post-treatment or on-treatment biopsies is important
to develop rational combination strategies for these immune-modulating drugs
she said. The presurgical clinical trials, also called window of opportunity
trials, allow researchers to learn a lot from a small number of patients to
guide the design of larger trials, Sharma said.
and Their Inhibitors
Negative checkpoint regulators (NCRs)
are molecules that restrict the ability of the
T-cells to effectively mount an immune attack against the tumor cells. Examples
of negative checkpoint regulators include CTLA-4, PD-1
expressed on T-cells.
They act in
to decrease immune response. Under physiological conditions,
these dampen T-cell activity
, and are important in reducing inflammatory
tissue damage and preventing autoimmune disease.
2 NCR inhibitors
of interest include
ipilimumab and nivolumab
, widely researched.
are monoclonal antibodies against CTLA-4
(ipilimumab) or PD-1/PD-L1
(i.e. nivolumab) can activate the immune system
, enhancing T-cell
proliferation and activity against tumors.
Limitations of these Agents When Used
- As mentioned earlier, ipilimumab a CTLA-4 inhibitor
increases T-cell entry into the tumor milieu, but at the same time increased the expression of 2 other
NCRs, namely PD-1 and V-domain immunoglobulin
(Ig)-containing suppressor of T-cell activation (VISTA), both of which once again down regulate the immune
response against the tumor, making ipilimumab ineffective.
- Interestingly, PD-1 inhibitors such as nivolumab cannot act if there is no T-cell
infiltration within the tumor.
Future Research Plans
- A clinical trial using ipilimumab
and nivolumab combination is being planned by Dr Sharma and her team, and
will enlist 90 volunteers nationally
- An inhibitor for VISTA is undergoing
phase I clinical trial to assess safety and dosage, but Sharma adds that
the drug could also be combined in prostate cancer clinical trials once
the Phase I is over.
- The prostate cancer combination
trial has protocols in place for recognizing and treating immune-related
reactions that could be associated with ipilimumab and nivolumab.
this study has shown the way for how future research in immunotherapy may need
to be approached to achieve optimal patient response.
- Immune Checkpoint Inhibitors and Prostate Cancer: A
New Frontier? - (https:www.ncbi.nlm.nih.gov/pmc/articles/PMC4943092/)
- VISTA Is a Novel Broad-Spectrum Negative Checkpoint
Regulator for Cancer Immunotherapy - (https:www.ncbi.nlm.nih.gov/pmc/articles/PMC4085258/)
- Macrophage - (https:en.wikipedia.org/wiki/Macrophage)