Prostate cancer, PCa, is a significant cancer especially in
older men. It is more than likely a highly heterogeneous cancer and thus unlike
many of the others we have examined there may not be a single strategy. There
has been a significant amount of effort to try and determine if immunotherapy
can be applied to PCa. This is especially true in that it does metastasize to
the bone and many hematological cancers have been addressed by immunotherapy.
We have examined many details of PCa elsewhere and refer the reader to that
.
As Drake, has indicated:
Prostate cancer is not traditionally considered an
immunologically responsive malignancy like melanoma or renal cell carcinoma,
yet the prostate glands of men with cancer are frequently diffusely infiltrated
with both CD4 and CD8 T cells, and several factors suggest that adenocarcinoma
of the prostate might prove an attractive target for immunotherapy.
First among these is the slow-growing nature of the
disease, allowing time for immunological intervention to overcome immunosuppressive
factors1 in the tumor microenvironment and to mount a clinically meaningful
response.
Second, serum PSA level, while not a true surrogate
marker, is routinely utilized in clinical decision making, and can serve to
guide the development of immunotherapy approaches.
Third, both proteomic and microarray analyses of prostate
cancer progression have delineated a number of relatively tissue-specific
proteins that may serve as tumor/tissue antigens.
Finally, abundant preclinical data suggest that an
antitumor immune response can be elicited, particularly when active
immunotherapy is combined with maneuvers to mitigate tolerance such as immune
checkpoint blockade, androgen ablation, or radiotherapy.
At least five phase III immunotherapy trials have been
initiated in the context of metastatic, castrate-resistant prostate cancer, but
none have yet met their predetermined end points
PCa has had a limited success with immunotherapy but not as
successful as other cancers. We will argue that a main reason is the complex
genetic makeup of PCa. However, the current genetic/immunological tool box
available may offer some new options.
The Prostate
The prostate is a glandular organ which appears upon
microscopic examination as a multiplicity of glands with muscle, nerve, blood, and
other stromal and parenchymal tissues. It has a high incidence of cancer as men
age and the cancers for the most part are indolent, namely have low chance of
metastasis, yet a fraction show highly aggressive behavior. Also an alleged
precursor of PCa, prostate cancer, is High Grade Prostate Intraepithelial
Neoplasia, an inflammatory disorder wherein the existing glandular regions
generally composed of basal and luminal cells, demonstrate significant growth
within the gland itself. It has been argued that this is a natural precursor to
PCa but we have demonstrated that the conclusion has significant exceptions.
Yet we know that inflammation is a driver to cancers and there thus is a
putative correlation but not a causation. (See Nunzio et al):
Evidence in the peer-reviewed literature suggested that
chronic prostatic inflammation may be involved in the development and
progression of chronic prostatic disease, such as BPH and PCa, although there
is still no evidence of a causal relation. Inflammation should be considered a
new domain in basic and clinical research in patients with BPH and PCa.
PCa is quite complex on a genetic basis. Berger et al have
discussed this at length. They state:
Prostate cancer is the second most common cause of male
cancer deaths in the United States. Here we present the complete sequence of
seven primary prostate cancers and their paired normal counterparts. Several
tumors contained complex chains of balanced rearrangements that occurred within
or adjacent to known cancer genes.
Rearrangement breakpoints were enriched near open
chromatin, androgen receptor and ERG DNA binding sites in the setting of the
ETS gene fusion TMPRSS2-ERG, but inversely correlated with these regions in
tumors lacking ETS fusions. This observation suggests a link between chromatin
or transcriptional regulation and the genesis of genomic aberrations. Three
tumors contained rearrangements that disrupted CADM2, and four harbored events
disrupting either PTEN (unbalanced events), a prostate tumor suppressor, or
MAGI2 (balanced events), a PTEN interacting protein not previously implicated
in prostate tumorigenesis. Thus, genomic rearrangements may arise from
transcriptional or chromatin aberrancies to engage prostate tumorigenic
mechanisms.
We have further examined this in detail in McGarty, Prostate
Cancer (2012). Now in 2009 Drake stated:
Prostate cancer is not traditionally considered an
immunologically responsive malignancy like melanoma or renal cell carcinoma,
yet the prostate glands of men with cancer are frequently diffusely infiltrated
with both CD4 and CD8 T cells, and several factors suggest that adenocarcinoma
of the prostate might prove an attractive target for immunotherapy.
First among these
is the slow-growing nature of the disease, allowing time for immunological
intervention to overcome immunosuppressive factors in the tumor
microenvironment and to mount a clinically meaningful response.
Second, serum PSA level, while not a true surrogate
marker, is routinely utilized in clinical decision making, and can serve to
guide the development of immunotherapy approaches.
Third, both proteomic and microarray analyses of prostate
cancer progression have delineated a number of relatively tissue-specific
proteins that may serve as tumor/tissue antigens.
Finally, abundant preclinical data suggest that an
antitumor immune response can be elicited, particularly when active
immunotherapy is combined with maneuvers to mitigate tolerance such as immune
checkpoint blockade, androgen ablation, or radiotherapy.
At least five phase III immunotherapy trials have been
initiated in the context of metastatic, castrate-resistant prostate cancer, but
none have yet met their predetermined end points
Drake was noting the potential for immunotherapeutic approaches
for this solid tumor. It is well known that the prostate is subject to various
inflammatory factors and that these factors have been linked to cancer changes.
The counter would be to examine using the immune responses to address the
changes. As we noted in melanoma, when observed, a melanoma often has an
accumulation of T cells, CTLs, indicating the natural defense mechanism.
On the other hand, it is intriguing to note the significant
impact that inflammation has on PCa and that immune response are present but
not yet active.
Current Techniques; Dendritic
One of the earliest treatments of PCa using an
immunotherapeutic approach is to use the patient's dendritic cells and prime
them. Recall that the dendritic cells are out in the body searching for
intruders. When they find one they then bring it back to the immune system for
presenting and for activating the immune system. Thus, rather than modifying a
T cell or an NK cell directly, the approach seeks to "prime" the
dendritic cells which will then start the immune response. This is an example
of examining the many entry points into using the immune system.
As Westdorp et al note:
Prostate cancer (PCa) is the most common cancer in men
and the second most common cause of cancer-related death in men. In recent
years, novel therapeutic options for PCa have been developed and studied
extensively in clinical trials. Sipuleucel-T is the first cell-based
immunotherapeutic vaccine for treatment of cancer. This vaccine consists of
autologous mononuclear cells stimulated and loaded with an immunostimulatory
fusion protein containing the prostate tumor antigen prostate acid posphatase.
The choice of antigen might be key for the efficiency of
cell-based immunotherapy. Depending on the treatment strategy, target antigens
should be immunogenic, abundantly expressed by tumor cells, and preferably
functionally important for the tumor to prevent loss of antigen expression.
Autoimmune responses have been reported against several antigens expressed in
the prostate, indicating that PCa is a suitable target for immunotherapy.
In this review, we will discuss PCa antigens that exhibit
immunogenic features and/or have been targeted in immunotherapeutic settings
with promising results, and we highlight the hurdles and opportunities for
cancer immunotherapy.
The authors above then consider a collection of putative
prostate antigens useful for applications of multiple approaches.
|
Antigen
|
Function
|
Action
|
|
PSA
|
PSA Serine
protease which cleaves high molecular weight proteins into smaller peptides,
resulting in the necessary liquification for spermatozoa to swim freely
|
Stimulates
CTL
Produces
cytokines
|
|
PAP
|
PAP Protein tyrosine
phosphatase which enhances the mobility of sperm
|
Stimulates CTL
|
|
PSMA
|
Folate
hydrolase activity
|
Presented
on cell surface. Elevated in PCa and HGPIN
|
|
PSCA
|
Unknown, overexpressed by most
PCas
|
T-cell activation and proliferation
|
|
MUC-1
|
Limiting
the activation of inflammatory response.
|
T-cell proliferation
|
|
NY-ESO-1
|
Unknown, expressed in a variety
of tumors
|
CTLs and antibody-mediated
responses
|
|
MAGE-A
|
Down-regulates
p53 function through histone deacetylase recruitment
|
Stimulates
CTLs in vivo
|
|
AKAP-4
|
Binding protein involved in
cytoskeletal regulation and organization by affecting cyclic AMP-dependent protein
kinase-A
|
Stimulated CTLs in vitro
|
Now for the dendritic cell targets they employ PAP as above
as well as GM-CSF. The dendritic cells mature in a solution with a fusion
protein (PA2024). The result is returned to the patient.
As Drake noted in 2009:
One of the few immunotherapy agents in late-stage
development for prostate cancer is Sipuleucel-T. In this approach, patients
undergo plasmapheresis, and a personalized immunotherapy product is produced by
culturing a patient’s peripheral blood monocytes with a proprietary protein
that couples granulocyte macrophage colony-stimulating factor with a target
antigen (PAP).
Phase I and phase III trials of Sipuleucel-T have been
reported, with encouraging results. Clinical development of this agent is pivotal
on a large (500 patients) randomized placebo-controlled phase III trial
(ImPACT; Immunotherapy Prostate Adenocarcinoma Treatment) which completed
accrual in October 2007, and for which additional survival data are expected
sometime this year (see Note Added in Proof).
In addition, considerable clinical development has
focused on a viral vector approach in which PSA itself is targeted using
sequential injections with recombinant vaccinia and fowlpox constructs. Here,
both constructs have been engineered to include a number of costimulatory
molecules in an effort to augment an immune response.
As Jahnisch et al note:
Dendritic cells (DCs) are professional antigen-presenting
cells (APCs), which display a unique capacity to induce, sustain, and regulate
T-cell responses. In tumor setting, DCs circulate through the blood and migrate
to tumor tissues, where they interact with malignant cells. Immature DCs are
particularly efficient in the uptake of tumorderived material. DC maturation is
induced by tumorderived molecules such as heat shock proteins and high mobility-
group box 1 protein as well as proinflammatory cytokines produced by various
tumor-infiltrating immune cells.
During maturation DCs migrate from tumor tissues to
T-cell-rich areas of secondary lymphoid organs, where they activate
tumor-reactive CD8+ cytotoxic T lymphocytes (CTLs) and CD4+ T cells. CD8+ CTLs
efficiently recognize and destroy tumor cells, which expose peptides derived
from tumor-associated antigens (TAAs) in the complex with human leukocyte
antigen (HLA) class I molecules.
Clinical studies focusing on the adoptive transfer of
cytotoxic effector cells revealed tumor regression in cancer patients. CD4+ T
cells recognizing peptides in the context of HLA class II molecules also play
an important role in antitumor immunity. CD4+ T cells improve the capacity of
DCs to induce CTLs by the interaction between CD40 on DCs and CD40 ligand on
activated CD4+ T cells.
In addition, CD4+ T cells provide help for the
maintenance and expansion of CTLs by secreting cytokines such as interleukin
(IL)-2 and can eradicate tumor cells directly. Besides their extraordinary
capacity to induce and stimulate T-cell responses, DCs efficiently improve the
immunomodulatory and cytotoxic potential of natural killer cells, which
essentially contribute to the elimination of tumor cells.
Furthermore, DCs can also directly mediate tumor-directed
cytotoxicity. Owing to their various antitumor effects, DCs evolved as
promising candidates for vaccination protocols in cancer therapy
Now as Mellman et al note:
While Provenge is clearly a cell-based therapy, there may
be other mechanisms involved. Although the majority (66%) of survivors showed
an antibody response to the fusion protein, the fraction of patients producing
antibodies that recognized endogenous PAP was much lower (28.5%).
Moreover, T-cell responses to either the fusion protein
or PAP were not associated with survival. These discrepancies might reflect a
limitation of monitoring antitumor immune responses in the peripheral blood
compared with the tumour microenvironment. However, they also raise the
possibility that other undefined factors in the cellular product may have an
important role. Further studies are required to understand the therapeutic
mechanism of Provenge, and to define the impact of the different
cell-processing procedures on the placebo product. The lack of tumour
shrinkage, the criterion typically used to gauge the efficacy of cancer
treatments, in the face of a survival benefit is surprising, but perhaps not
unexpected for immunotherapy. As seen pre-clinically, an effect on pre-existing
tumour due to immune manipulations can be delayed while an immune response
develops.
Furthermore, biopsies of metastases after vaccination in
some clinical trials revealed the presence of immune infiltrates that mediate
tumour destruction in association with extensive edema, which may be followed
by fibrosis46.
These histopathological findings suggest that monitoring
tumour size alone may be inadequate for assessing the overall therapeutic effects
of vaccination. As discussed later, these considerations apply to the
evaluation of CTLA-4 antibody blockade, highlighting the need to modify tumour
response criteria in light of new insights into the biology of immunotherapy.
Now Mellman et al make several key points as to the
dendritic approach. First, RESIST approaches measure tumor size and in classic
chemotherapy cases it does shrink. Yet as has been seen again and again in the
more sophisticated and targeted approaches the shrinking takes time as the
tumor, albeit present, it being attacked and killed off, albeit still visible
on say a CAT Scan. Second, there is the putative supposition that there are
other factors afoot. The latter we shall explore with the checkpoint
examination.
Checkpoint Targets
Checkpoints are simply receptor-ligand pairs which when
activated can inhibit the actions of T cells and other immune pathway actions.
As Topalian et al note:
The rapid-fire clinical successes from blocking CTLA-4
and PD-1, the first checkpoint receptors to be discovered, have opened prospects
for extending the potential of cancer immunotherapy by inhibiting more recently
discovered checkpoint ligands and receptors. It is clear that, despite some
commonalities, CTLA-4 and PD-1 have distinct patterns of expression, signaling
pathways, and mechanisms of action. Although discovered over 20 years ago,
there are still many unanswered questions about their biology, particularly in
the context of cancer.
The authors continue:
The immune system recognizes and is poised to eliminate
cancer but is held in check by inhibitory receptors and ligands. These immune
checkpoint pathways, which normally maintain self-tolerance and limit
collateral tissue damage during anti-microbial immune responses, can be
co-opted by cancer to evade immune destruction. Drugs interrupting immune
checkpoints, such as anti-CTLA-4, anti-PD-1, anti-PD-L1, and others in early
development, can unleash anti-tumor immunity and mediate durable cancer
regressions. The complex biology of immune checkpoint pathways still contains
many mysteries, and the full activity spectrum of checkpoint-blocking drugs,
used alone or in combination, is currently the subject of intense study.
Thus, the issue would be; what other check points are there
and how can they be addressed? From Kono we have the following Table which
presents some putative targets:
|
Target
|
Biological
function
|
Antibody
(fusion protein)
|
Phase
|
Cancer
type
|
|
CTLA4
|
Inhibitory receptor
|
Ipilimumab
|
FDA approved Phase II and III
|
melanoma, multiple cancers
|
|
PD1
|
Inhibitory receptor
|
MDX-1106 MK3475 CT-011 AMP-224
|
Phase I/II Phase I Phase I Phase I
|
melanoma, renal, lung multiple cancers multiple cancers multiple
cancers
|
|
PDL1
|
Ligand for PD1
|
MDX-1105
|
Phase I
|
multiple cancers
|
|
LAG3
|
Inhibitory receptor
|
IMP321
|
Phase II
|
breast cancer
|
|
B7-H3
|
Inhibitory ligand
|
MGA271
|
Phase I
|
multiple cancers
|
|
B7-H4
|
Inhibitory ligand
|
|
|
Preclinical
|
|
TIM3
|
Inhibitory receptor
|
|
|
Preclinical
|
From the recent work of Beer et al:
Ipilimumab is a fully human monoclonal immunoglobulin G1
antibody that increases antitumor T-cell responses by binding to cytotoxic
T-lymphocyte antigen 4.17-19 Blocking by ipilimumab of the T-cell negative
regulator cytotoxic T-lymphocyte antigen 4 allows CD28 and B7 interactions,
which result in T-cell activation; proliferation; tumor infiltration; and
ultimately, cancer cell death. Treatment with ipilimumab, as a single agent or
in combination with dacarbazine, provided significant survival benefit in two
phase III trials of advanced melanoma. Of note, approximately 20% of
ipilimumab-treated patients with melanoma experienced longterm survival
We have seen this in detail when examining the melanoma
therapeutic approaches. Now the application of this to PCa is interesting and
challenging. Melanoma is an aggressive and rapidly growing cancer and it is
well known that it often evokes an immune response when examined on biopsy. In
contrast PCa is quite different. Melanoma is derived from melanocytes which have
developed from the neural crest. PCa is exocrine glandular. The results of the
Beer trial were not conclusive.
More recently Schweizer and Drake (2014) noted:
Since the approval of sipuleucel-T for men with
metastatic castrate resistant prostate cancer in 2010, great strides in the
development of anti-cancer immunotherapies have been made. Current drug
development in this area has focused primarily on antigen specific [i.e. cancer
vaccines and antibody based therapies)] or checkpoint inhibitor therapies, with
the checkpoint inhibitors perhaps gaining the most attention as of late.
Indeed, drugs blocking the inhibitory signal generated by
the engagement of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell
death-1 (PD-1) found on T-cells has emerged as potent means to combat the immunosuppressive
milieu. The anti-CTLA-4 monoclonal antibody ipilimumab has already been approved
in advanced melanoma and two phase III trials evaluating ipilimumab in men with
metastatic castrate-resistant prostate cancer are underway.
A phase III trial evaluating ProstVac- VF, a
poxvirus-based therapeutic prostate cancer vaccine, is also underway. While
there has been reason for encouragement over the past few years, many questions
regarding the use of immunotherapies remain.
Namely it is unclear what stage of disease is most likely
to benefit from these approaches, how best to incorporate said treatments with
each other and into our current treatment regimens and which therapy is most
appropriate for which disease. Herein we review some of the recent advances in
immunotherapy as related to the treatment of prostate cancer and outline some
of the challenges that lie ahead.
More recently Martin et al noted:
Primary prostate cancers are infiltrated with PD-1
expressing CD8+ T cells. However, in early clinical trials, men with mCRPC did
not respond to PD-1 blockade as a monotherapy. One explanation for this
unresponsiveness could be that prostate tumors generally do not express PD-L1,
the primary ligand for PD-1.
However, lack of PD-L1 expression in prostate cancer
would be surprising, given that PTEN loss is relatively common in prostate
cancer and several studies have shown that PTEN loss correlates with PD-L1
up-regulation - constituting a mechanism of innate immune resistance. This
study tested whether prostate cancer cells were capable of expressing PD-L1,
and whether the rare PD-L1 expression that occurs in human specimen's
correlates with PTEN loss…These studies show that some prostate cancer cell
lines are capable of expressing PD-L1.
However, in human prostate cancer, PTEN loss is not
associated with PD-L1 expression, arguing against innate immune resistance as a
mechanism that mitigates anti-tumor immune responses in this disease.
Unfortunately, the results are less than positive. They seem
to agree with the prior results.
Options
There are many options available for dealing with PCa but
the efficacy of these known options is at best problematic. Yoo et al have
summarized the recent (2016) immunotherapeutic options for PCa. They note the
following:
Despite advances in treatment of prostate cancer,
curative therapy is not yet available for CRPC. Novel therapeutic options have
thus been sought, and vaccines, immunotherapy, and gene based therapy are
considered to be attractive candidates in this respect.
Up to now, sipuleucel-T is the only such treatment
approved by the Food and Drug Administration.
…the authors will briefly introduce investigational
vaccines, immunotherapy, and gene-based therapy for CRPC.
5.1. Vaccine
GX301is a dual-adjuvant telomerase vaccine. GX301 is
reported to be safe and highly immunogenic in patients with prostate cancer. A
Phase II randomized trial is underway.
Prostvac is a vector based therapeutic cancer vaccine. A
Phase II study reported that prostvac was well tolerated and it improved
overall survival compared with control vectors (25.1 months vs. 16.6 months) in
patients with minimally symptomatic CRPC. However, another Phase II study,
which evaluated the effect of the combination of docetaxel and prostvac, failed
to show improvements in overall survival; this lack of positive results may be
due to limited accrual of patients. Investigation on the relative efficacy of
simultaneous versus sequential docetaxel þ prostvac is currently ongoing.
DCVAC is an autologous dendritic cell-based vaccine. In a
Phase I and II trial, combination chemoimmunotherapy with DCVAC and docetaxel
resulted in longer than expected survival (19 months vs. 11.8 months) without
significant complications. A Phase III study, evaluating the merits of DCVAC
when added to standard chemotherapy, is due to commence.
Vaccines have been examined by many over the past few years.
As noted, perhaps multi-therapeutic methods may also prove beneficial.
5.2. Immunotherapy
Ipilimumab
is a monoclonal antibody that blocks the activity of CTLA-4 (cytotoxic
T-lymphocyte-associated protein 4) and was approved by the Food and Drug
Administration for the treatment of melanoma in 2011. As preclinical and
clinical studies suggested that radiotherapy might activate the immune system
in patients with prostate cancer, a Phase III trial of ipilimumab in addition
to radiotherapy for metastatic CRPC patients was initiated. However, this Phase
III study did not show any improvement in overall survival after radiotherapy
followed by ipilimumab, compared with radiotherapy followed by placebo.
Currently, combination trials with abiraterone, ADT,
sipuleucel-T, and prostvac are underway. 177Lu-J591, a humanized monoclonal
antibody, was primarily developed in a radiolabeled form for PET, binding to
the extracellular domain of prostate-specific membrane antigen (PSMA). After
binding to PSMA, the 177Lu-J591ePSMA complex undergoes endocytosis and is
accumulated in prostate cancer cells.
In this regard, 177Lu-J591J591 is considered to be a
potential carrier for cytotoxic drug conjugates to maximize therapeutic
effectiveness and a promising agent for radioimmunotherapy. Currently, a Phase
2 clinical trial is in the process of patient recruitment.
Immunotherapy via check point inhibitors has become quite
popular after the success in melanoma therapy. It has not, however, seen as
significant in PCa.
5.3. Gene-based therapy
Olaparib, recently approved for treating ovarian cancer
with BRCA1/2 mutations, is a poly-ADT-ribose polymerase inhibitor.
Poly-ADT-ribose polymerase is involved in the DNA repair process, and genomic
aberrations observed in CRPC are thought to confer sensitivity to
poly-ADTribose polymerase inhibitors. In recent studies, olaparib showed a
considerable response rate of 33% in post-docetaxel prostate cancer patients
with defects in DNA repair genes, and a Phase II trial has commenced.
Thus, the only accepted approach is the dendritic approach
that have been approved. The checkpoint approach has not yield any significant
positive result although trial continue.
Let us review the options.
Let us examine these in some further detail in the following
Table. In this Table, we lay out some options for consideration.
|
Approach
|
Mode of Operation
|
Issues/Opportunities
|
|
Dendritic
|
The dendritic cells are antigen
presenting cells. They manage to move throughout the body and identify
various potential pathogens.
|
This seems to be the first of the
putatively efficacious approaches in dealing with PCa.
|
|
CTL
|
Cytotoxic T Lymphocytes, Killer T cells, are the T cells
which are an integral part of the adaptive immune system.
|
CTL need targeting via Ab specific paths.
|
|
NK
|
NK cells are part of the innate
immune system, albeit being a lymphocyte lineage. They function by a
balancing act between activators and inhibitors.
|
NK cells are effective innate
killers of intruders. However, they can also release their killing cytokines
which in turn may do harm to cells.
|
|
Mab
|
Monoclonal antibodies, Mab, are fundamentally Ab designed
to recognize certain antigens, or epitopes, and attach to them and bring out
the adaptive immune system response.
|
Mabs require the identification of targets. These targets
must have some uniqueness.
|
|
CRISPR
|
CRISPRs allow for the editing of
genes for the inclusion or excision of segments of DNA.
|
CRISPRs are somewhat independent
of targets per se. They may have the ability to find alternative means for
attacking the PCa cells.
|
|
CAR T
|
CAR T cells are T cells which have been genetically
modified to attack specific targets which would normally be suppressed by MHC
surface molecules identifying the cell as self.
|
CAR T cells like Mabs need targets. This is another
example of identifying unique PCa cell targets.
|
|
Gene Drive
|
Gene Drives have been used in trying
to "drive" a specific gene into some species. They generally drive
at the embryo level, the fundamental stem cell level is you will, into a species.
However, one could consider this also being used to "drive" into T
cells or NK cells the ability to attack specific PCa cells.
|
Gene Drives can potentially drive
into the stem cells of the immune system. Instead of changing the total
species they can introduce self-replicating cells to attack the PCa.
|
|
CIK
|
Cytokine-induced killer (CIK) cells are polyclonal T
effector cells generated when cultured under cytokine stimulation. CIK cells
exhibit potent, non-MHC-restricted cytolytic activities against susceptible
tumor cells of both autologous and allogeneic origins .
|
CIK cells have shown to be effective is properly targeted.
They have not been so for PCa but perhaps their broader spectrum capability
for genetic markers may be useful.
|
Observations
Based upon some of the recent results there are several observations
worth examining. The most significant issue is the complexity of the PCa
genome. Thus, the main problem we believe in PCa is the complex nature of the
genetic makeup. As Gundem et al noted in 2015:
Cancers emerge from an ongoing Darwinian evolutionary
process, often leading to multiple competing sub-clones within a single primary
tumour. This evolutionary process culminates in the formation of metastases, which
is the cause of 90%of cancer-related deaths. However, despite its clinical
importance, little is known about the principles governing the dissemination of
cancer cells to distant organs. Although the hypothesis that each metastasis
originates from a single tumour cell is generally supported, recent studies
using mouse models of cancer demonstrated the existence of polyclonal seeding
from and inter-clonal cooperation between multiple sub-clones.
Here we sought definitive evidence for the existence of polyclonal
seeding in human malignancy and to establish the clonal relationship among
different metastases in the context of androgen deprived metastatic prostate
cancer. Using whole-genome sequencing, we characterized multiple metastases
arising from prostate tumour in ten patients. Integrated analyses of sub-clonal
architecture revealed the patterns of metastatic spread in unprecedented detail.
Metastasis-to-metastasis spread was found to be common, either through de novo
monoclonal seeding of daughter metastases or, in five cases, through the
transfer of multiple tumour clones between metastatic sites.
Lesions affecting tumour suppressor genes usually occur
as single events, whereas mutations in genes involved in androgen receptor
signalling commonly involve multiple, convergent events in different metastases.
Our results elucidate in detail the complex patterns of metastatic spread and
further our understanding of the development of resistance to
androgen-deprivation therapy in prostate cancer.
Namely many genetic changes are occurring continuously as
PCa progresses. Thus, seeking a single marker may be fruitless. Yet, the immune
approach can be designed to address the significant genetic complexity of PCa.
Namely by addressing a broad spectrum of possible cells as would be the case
with a CIK approach one could envision a treatment akin to a chronic disorder.
References
1.
Beer, T., et al, Randomized,
Double-Blind, Phase III Trial of Ipilimumab Versus Placebo in Asymptomatic or
Minimally Symptomatic Patients with Metastatic Chemotherapy-Naïve
Castration-Resistant Prostate Cancer, Jrl Clin Onc, V 34, 2016.
2.
Berger, M., et al, The genomic
complexity of primary human prostate cancer, Nature Geb 2011, pp 214-220.
3.
Drake, C., Immunotherapy for
Prostate Cancer: Walk, Don’t Run, Jrl Clin Onc V 27 N 25 Sept 2009.
4.
Emens, L. It’s TIME for a
biomarker-driven approach to cancer immunotherapy, Journal for ImmunoTherapy of
Cancer (2016) 4:43
5.
Farcona, S., et al, Cancer
immunotherapy: the beginning of the end of cancer? BMC Medicine (2016) 14:73
6.
Finn, A., Cancer Immunology, NEJM,
June 2008
7.
Freytag, S., et al, Prostate Cancer
Gene Therapy Clinical Trials, Molecular Therapy, vol. 15 no. 6, 1042–1052 June
2007
8.
Gundem, G., et al, The evolutionary
history of lethal metastatic prostate cancer, Nature, April 2015 Vol 520
9.
Harris, T., C. Drake, Primer on
tumor immunology and cancer immunotherapy, Journal for ImmunoTherapy of Cancer
2013, 1:12
10.
Jahnisch, H., et al, Dendritic
Cell-Based Immunotherapy for Prostate Cancer, Clinical and Developmental
Immunology, Volume 2010, Article ID 517493
11. Kono, K., Current status of cancer immunotherapy, JSRM/Vol10
No.1, 2014.
12. Linn, C., K., Hui, Cytokine-Induced NK-Like T Cells: From Bench
to Bedside, Journal of Biomedicine and Biotechnology Volume 2010, Article ID
435745, 8 pages
13.
Martin, A., et al, Paucity of PD-L1
Expression in Prostate Cancer: Innate and Adaptive Immune Resistance, Prostate
Cancer Prostatic Dis. 2015 December; 18(4): 325–332
19.
Mellman, I., et al, Cancer
immunotherapy comes of age, Nature, Dec 2011 Vol 480.
20.
Nunzio, C., et al, The
Controversial Relationship Between Benign Prostatic Hyperplasia and Prostate
Cancer: The Role of Inflammation, Euro Urolog 2011.
21.
Schoenborn, J., et al, Genomic
Profiling Defines Subtypes of Prostate Cancer with the Potential for
Therapeutic Stratification, Clin Cancer Res; 19(15) August 1, 2013
22.
Schweizer, M., C. Drake, Immunotherapy
for Prostate Cancer – Recent Developments and Future Challenges, Cancer
Metastasis Rev. 2014 September; 33(0): 641–655
23.
Taichman, R., et al, The evolving
biology and treatment of prostate cancer, The Journal of Clinical Investigation
http://www.jci.org Volume 117 Number 9 September 2007
24.
Topalian, S., et al, Immune
Checkpoint Blockade: A Common Denominator Approach to Cancer Therapy, Cancer
Cell V 27, April 2015.
25.
Wada, S. et al, Sequencing CTLA-4
blockade with cell-based immunotherapy for prostate cancer, Journal of
Translational Medicine 2013, 11:89
26.
Westdorp, H., et al, Immunotherapy
for prostate cancer: lessons from responses to tumor-associated antigens, Front
in Immuno, 6 May 2014.
27.
Yoo, S., et al, New drugs in
prostate cancer, Prostate Int 4 (2016) 37e42.
Posts
