Thursday, February 9, 2017

Some Thoughts on Prostate Cancer Immunotherapy

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[1].

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.

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 Protein tyrosine phosphatase which enhances the mobility of sperm

Stimulates CTL
Folate hydrolase activity
Presented on cell surface. Elevated in PCa and HGPIN

Unknown, overexpressed by most PCas

T-cell activation and proliferation
Limiting the activation of inflammatory response.

T-cell proliferation
Unknown, expressed in a variety of tumors
CTLs and antibody-mediated

Down-regulates p53 function through histone deacetylase recruitment

Stimulates CTLs in vivo
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:

Biological function
Antibody (fusion protein)
Cancer type
Inhibitory receptor
FDA approved Phase II and III
melanoma, multiple cancers
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
Ligand for PD1
Phase I
multiple cancers
Inhibitory receptor
Phase II
breast cancer
Inhibitory ligand
Phase I
multiple cancers
Inhibitory ligand

Inhibitory receptor


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.


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[2] 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.

Mode of Operation
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.
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 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.
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.
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 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.
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[3].

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.


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.


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