Immunotherapy for Prostate Cancer: Where Do We Go From Here?-PART 2: Checkpoint Inhibitors, Immunotherapy Combinations, Tumor Microenvironment Modulation, and Cellular Therapies

Therapeutic approaches that harness the power of the immune system to eliminate cancer cells have produced a paradigm shift in the management of a variety of malignancies. Prostate cancer has been a particularly active area of investigation in cancer immunotherapy, with significant laboratory and clinical evidence suggesting that this disease can be a viable target for cytotoxic immune cells. In the first article of this series, we discussed the diverse vaccination approaches that have been employed to prime native antigen-specific responses against prostate cancer, highlighting successes such as sipuleucel-T, as well as the significant challenges that remain. Here we focus on alternative methods of harnessing both adaptive and innate antitumor immunity to target prostate cancer cells. Approaches that enhance the activation of T cells, modulation of the tumor microenvironment to abrogate its inherent immunosuppressive mechanisms, and engineering of antigen-specific antibody and cellular products to target tumor cells will be discussed. We will then look ahead to provide a perspective on how this growing collection of immunotherapeutic approaches may ultimately be combined to target prostate cancer from a variety of angles.

Introduction

Prostate cancer is the most commonly diagnosed malignant tumor in American men and the second leading cause of cancer-related mortality.[1] Relapse is estimated to occur in 30% of cases that are localized at presentation,[2] and resistance to chemohormonal therapy in the metastatic setting remains a significant cause of morbidity and mortality. While the nonessential nature of prostate tissue, presence of organ-specific tumor associated antigens, and generally favorable growth kinetics of this disease all argue for increased vulnerability of cancer cells to immunologic elimination,[3] a variety of inherent genetic characteristics and dynamic mechanisms of adaptive immune resistance facilitate tumor immune evasion. Cytotoxic T-cell functioning is regulated by signaling via a varied collection of costimulatory receptors that act to modulate signaling through the T-cell receptor (TCR). The advent of antibodies capable of blocking negative regulatory molecules on T cells, thereby inducing enhanced cell activation and greater adaptive antitumor immunity, has transformed the management of a variety of cancer subtypes. Tumors of the prostate, however, are known to have a relative paucity of cytotoxic T cells within the tumor microenvironment and in general have a reduced tumor mutation burden compared with other tumor types.[4] This reduced frequency of mutations may limit the number of novel tumor-associated antigens available for presentation to T cells, thereby limiting the pool of T cells capable of significant tumoricidal activity. Consequently, strategies that aim to expand the collection of tumor-specific T cells, enhance the release of prostate tumor antigens, or make the intratumoral environment more accessible to T cells are all being investigated alone and in concert with checkpoint inhibition.

Immune Checkpoint Inhibition

The activation of the CD28 costimulatory pathway in T cells is negatively regulated by cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) competing with CD28 for binding to B7 ligands. Ipilimumab is a humanized monoclonal antibody that blocks CTLA-4, thereby increasing CD28 signaling and enhancing the effector T-cell response.[5,6] Some of the earliest clinical trials demonstrating clinical activity of ipilimumab were conducted in prostate cancer patients,[7,8] but phase III placebo-controlled trials in both docetaxel-naive and post-docetaxel metastatic castration-resistant prostate cancer (mCRPC) settings did not show improvement in the primary endpoint of overall survival (OS).[9,10] While these trials demonstrated modest advantages in progression-free survival and prostate-specific antigen (PSA) response rates with ipilimumab, over one-quarter of patients in both trials experienced grade 3/4 immune-related adverse events when treated with 10 mg/kg of ipilimumab, with multiple deaths due to drug-related toxicity. A post-hoc analysis of subgroups in the trial treating post-docetaxel mCRPC patients with ipilimumab after bone-directed radiation found that favorable prognostic factors, such as alkaline phosphatase concentration of < 1.5 times the upper limit of normal, hemoglobin of ≥ 11.0 g/dL, and no visceral metastases, demonstrated an improvement in OS (hazard ratio, 0.62; 95% CI, 0.45%–0.86; P = .0038).[10] Additionally, while rare, there are case reports of sustained complete remissions among patients treated in these trials.[11] It is clear that ipilimumab maintains activity in the mCRPC setting, but these trial results highlight the need to identify biomarkers that select the patients most likely to benefit and those most susceptible to severe toxicities. Mitigation of severe toxicities through alternate dosing and improved selection may in turn help to improve OS.

The recognition that multiple immunosuppressive mechanisms act in concert to prevent antitumor response and that checkpoint inhibition is likely most effective when tumor antigens are recognizable to effector T cells has prompted many combination immunotherapy approaches involving checkpoint inhibitors. Phase I studies of ipilimumab and granulocyte-macrophage colony-stimulating factor (GM-CSF) showed the combination to have suitable safety and the capacity to increase activation of circulating CD8+ T cells while inducing PSA response in 25% of patients.[12] PSA responses were also noted in early trials of ipilimumab in combination with vaccines GVAX and PROSTVAC (PSA-TRICOM). The phase I trial of GVAX in conjunction with ipilimumab identified 3 mg/kg of ipilimumab as a tolerable dose, with 25% of patients achieving a > 50% PSA response.[13] While GVAX has not progressed further in clinical development, this trial provided an opportunity to address the question of biomarkers predictive of response to combination immunotherapy. Secondary analyses suggested high frequencies of activated CTLA-4+ or programmed death 1 (PD-1)+ T helper (Th) cells, treatment-induced conventional dendritic cell (DC) activation, low pretreatment monocytic myeloid-derived suppressor cells (MDSCs), and low pretreatment regulatory T cells (Tregs) were predictive of OS benefit in this limited treatment cohort.[14,15] The phase I combination trial of ipilimumab + PROSTVAC was notable for a significant subset of patients (6/24) who experienced > 50% PSA decline and a robust median OS of 31.6 months.[16]

Radiation may prime a T-cell immune response by damaging DNA; increasing expression of major histocompatibility complex class I (MHC-I), Fas, intercellular adhesion molecule 1, and targetable costimulatory receptors such as programmed death ligand 1 (PD-L1); expanding the number of tumor-associated antigens; and increasing cytokines such as tumor necrosis factor α and interleukin (IL)-6.[17] Preclinical models in breast and colon cancer first revealed that combining anti–CTLA-4 monoclonal antibodies with radiation leads to an immune-mediated abscopal effect characterized by an increase in tumor-infiltrating lymphocytes (TILs).[18] Because radiation has a well-established role in prostate cancer management, these data support the concept of administering radiation therapy in conjunction with checkpoint blockade in prostate cancer. A review of active trials shows a diverse range of ipilimumab combinations currently being tested. These include neoadjuvant studies (ClinicalTrials.gov identifiers: NCT02113657, NCT01194271, NCT02506114), combinations with sipuleucel-T (NCT01832870, NCT01804465), with PROSTVAC (NCT00113984), with GM-CSF (NCT00064129), with DC vaccines (NCT02423928), with various modalities of androgen deprivation therapy (ADT) (NCT01377389, NCT01498978, NCT00170157, NCT01688492, NCT02020070, NCT02703623), and with PD-1 blockade (NCT03061539, NCT02985957, NCT02601014).

PD-1 is a type I transmembrane glycoprotein expressed on the T-cell surface that interacts with its ligand, PD-L1, to inhibit T-cell activity. While CTLA-4 inhibits T-cell activation during the priming phase of T-cell activation, the inhibitory activity of PD-1 occurs during the effector phase. Antibodies targeting the PD-1 pathway, such as nivolumab and pembrolizumab, and more recently PD-L1 inhibitors such as atezolizumab, have received regulatory approval for use in other tumor types.[19-22] Early data from phase I trials of nivolumab demonstrated no objective responses in 25 heavily pretreated mCRPC patients.[23,24] The low response rate may be due to the fact that PD-L1 expression, which positively correlates with clinical response, is minimal in prostate cancer.[25] Despite the lack of response in early studies, the PD-1/PD-L1 axis remains an area of therapeutic interest in specific clinical contexts, namely, in advanced prostate cancer and in combination with other therapeutic modalities. Recent reports demonstrated that patients progressing on androgen receptor blockade with enzalutamide exhibit increased PD-L1/2+ DCs in blood and a high frequency of PD-1+ T cells.[26] Subsequent studies have demonstrated clinical responses to pembrolizumab in mCRPC patients exhibiting PD-L1 upregulation during treatment with androgen blockade.[27,28] A similar study with avelumab, an anti–PD-L1 antibody, showed long-term radiographic stabilization in 7 of 18 patients.[29] Consequently, a global phase III randomized, multicenter trial (NCT03016312) is underway to evaluate the efficacy and safety of the combination of the anti–PD-L1 antibody atezolizumab and enzalutamide vs enzalutamide alone in the post-abiraterone setting.

Vaccinations are also being utilized in combination with anti–PD-1 checkpoint inhibitors in prostate cancer. The prostatic acid phosphatase–encoding DNA vaccine pTVG-HP is being tested in combination with pembrolizumab after preclinical models demonstrated T-cell PD-1 upregulation after vaccination. Preliminary results suggest that this combination is safe, and there are encouraging reports of PSA declines with treatment (NCT02499835). A similar investigation is evaluating the use of rilimogene, a poxviral vaccine targeting PSA, and nivolumab (NCT02933255), while other trials are also looking at novel combinations with immunomodulatory agents and checkpoint inhibitors (NCT02616185). Attenuated Listeria engineered to express tumor-associated antigen is also being utilized in combination with PD-1 checkpoint blockade ADXS31-142 in a phase I clinical trial (NCT02325557).

A recent report suggests that 11.8% of patients with mCRPC have germline DNA repair mutations,[30] and it is thought that 25% to 30% of men with sporadic mCRPC harbor such defects in DNA repair machinery.[31] It has been hypothesized that increased cytosolic double-stranded tumor-associated DNA resulting from poly (ADP-ribose) polymerase (PARP) inhibition may increase tumor antigenicity.[32] Preclinical studies demonstrated PARP-mediated upregulation of PD-L1, with subsequent antitumor activity seen with administration of an anti–PD-L1 antibody.[33] Preliminary data from a combination of durvalumab (an anti–PD-L1 antibody) and a PARP inhibitor showed encouraging results, with PSA declines > 50% in 7/16 prostate cancer patients who were receiving treatment for > 2 months.[34] Importantly, these responses were in heavily pretreated patients, and activity was seen even in patients without DNA-repair mutations. Radium-223, a radiopharmaceutical indicated for use in mCRPC, has shown immunomodulatory effects in preclinical data.[35] An ongoing phase I study is evaluating the combination of radium-223 and atezolizumab in mCRPC (NCT02814669), and another is evaluating the combination of radium-223 and sipuleucel-T (NCT02463799). Currently, many clinical trials are exploring the role of PD-1/PD-L1–directed therapy in diverse combinations in the neoadjuvant, hormone-sensitive prostate cancer, and mCRPC settings. These include checkpoint blockade in conjunction with radium (NCT03093428), with vaccines (NCT02499835, NCT02933255, NCT03024216), with CTLA-4 blockade (NCT03204812, NCT02643303), with PARP inhibitors (NCT03338790, NCT02484404), and with novel immunomodulatory compounds (NCT02009449, NCT02655822).

Immune checkpoint targets beyond CTLA-4 and PD-1 are also generating increased interest in prostate cancer. For example, evaluation of resected tumors following a pretreatment course of ipilimumab and ADT not only showed greater immune infiltrate in tumor tissue but also upregulation of PD-L1 and V-domain immunoglobulin suppressor of T-cell activation (VISTA) inhibitory molecules,[36] suggesting the possibility of sequential checkpoint antibody regimens in future trials. B7-H3/4, T-cell immunoglobulin domain and mucin domain 3 (TIM-3), and other checkpoints are also being evaluated as targets for future therapies, likely in combination with other immunomodulatory agents. Ultimately, a deeper understanding of the biology of the tumor microenvironment (TME) and identification of specific biomarkers predictive of response to tailored therapies will be critical to pairing the appropriate combination to a particular patient. One can envision biopsy-driven protocols that classify patients according to the composition of a tumor’s baseline immune infiltrate, followed by assignment to specific therapies based on such parameters as Th1 immunity, PD-L1 expression, exclusion of T cells from the tumor, MHC-I expression, and presence or absence of other immune inhibitory factors and cell populations.

Modulation of the TME

The tendency of prostate cancer to metastasize to bone has particular implications for immunotherapy, since a variety of factors contribute to making bone metastases sites of therapeutic resistance and immune suppression. Tumor cells enhance osteoblast and osteoclast activity, which in turn releases growth factors that fuel tumor growth; this so-called “vicious cycle” is driven in part by transforming growth factor beta (TGF-β), which also suppresses the immune response in a variety of ways.[37-40] The relative hypoxia of the hematopoietic stem cell niche occupied by cancer cells migrating to bone enhances their stem-like properties, dampens antigen presentation, and suppresses natural killer (NK) cell cytotoxicity.[41] Additionally, this environment is rich in suppressive Tregs, MDSCs, and tumor-associated macrophages (TAMs). Investigation continues into agents that may target these immunosuppressive cell populations in the bone microenvironment, including agents that inhibit myeloid cell recruitment by blocking chemokines such as colony stimulating factor 1 and CCL2.[42-44] Bisphosphonates and RANKL inhibitors are believed to suppress Treg activity and shift TAMs away from tumor-promoting M2 phenotypes; they are being explored for synergistic activity in combination with immune checkpoint blockade.[45,46]

Additional strategies have sought to augment antitumor immunity through manipulation of the immune milieu of the TME via immunomodulatory drugs. Lenalidomide is an oral thalidomide analog that has antiangiogenic, antiinflammatory, and immunomodulatory effects. Evaluation of lenalidomide in mCRPC produced a PSA decline in 13/27 patients (48%), but this was complicated by significant hematologic grade 3/4 toxicities.[47] A subsequent phase I/II study of lenalidomide and GM-CSF showed only modest clinical activity.[48] Lenalidomide was also tried in addition to docetaxel in the MAINSAIL trial, but this combination unfortunately resulted in worse OS than chemotherapy alone.[49] The significant toxicities and disappointing overall response in combination therapy trials have dampened clinical interest in lenalidomide and may limit its further development as an immunotherapy for prostate cancer.

Indoleamine 2,3-dioxygenase (IDO) catalyzes the breakdown of the essential enzyme tryptophan and is constitutively expressed in most human tumors. The resulting depletion of tryptophan and build-up of the toxic catabolite kynurenine promotes an immunosuppressive tumor microenvironment through a variety of mechanisms.[50] Consequently, there has been significant interest in developing inhibitors of the IDO pathway. They have been well tolerated and demonstrate promising synergy/clinical activity when given in conjunction with checkpoint inhibition. Promising response rates in non–small-cell lung cancer and melanoma with pembrolizumab plus the IDO inhibitor epacadostat were recently reported,[51,52] leading to exploration of this combination in a phase III trial in melanoma (NCT02752074) and a recently announced expansion of this phase III program into non–small-cell lung, renal, bladder, and head and neck cancers. An alternate IDO inhibitor, indoximod, when given for at least 10 weeks after completion of sipuleucel-T, showed no significant difference in side effects compared with placebo. Although there was no difference in PSA progression or immune responses to the recombinant fusion protein (PA2024) used in sipuleucel-T production, an increased radiologic progression-free survival with indoximod compared with post–sipuleucel-T placebo was noted (10.3 vs 4.1 months).[53] Tasquinimod is an oral small molecular inhibitor of S100A9, an important regulatory protein found in the TME and on MDSCs. It is believed to exhibit its antineoplastic properties by inhibiting MDSC migration to the tumor and skewing tumor-associated macrophages toward an antiangiogenic M1 phenotype, via both vascular endothelial growth factor (VEGF)-direct and VEGF-independent antiangiogenic pathways.[54] Despite encouraging phase I and II results,[55,56] a phase III randomized, controlled trial of tasquinimod vs placebo in mCRPC with bone metastases[57] failed to significantly affect OS. The study authors cited the increased use of posttreatment salvage therapies such as abiraterone and enzalutamide in the placebo cohort and the possibility of more aggressive baseline characteristics in the tasquinimod cohort as possible explanations for the lack of OS advantage. Tasquinimod has also been studied as maintenance therapy following front-line docetaxel,[58] in conjunction with sipuleucel-T (NCT02159950), and in a phase I trial with cabazitaxel.[59]. Ultimately, the challenge of delivering the maximally tolerated dose of the agents in combination, apparently marginal additive efficacy, and the lack of OS improvement in the single-agent phase III trial halted further development of tasquinimod/chemotherapy combinations.

Angiogenic pathways have been implicated in tumor progression both through direct effects on vasculature and via an increasingly recognized role in the modulation of tumor-mediated immunosuppression. The tyrosine kinase inhibitor sunitinib showed encouraging results as monotherapy in early-phase trials of mCRPC, but randomized phase III results revealed no impact on OS.[60] Combinations of sunitinib and chemotherapy have not progressed beyond early-phase trials,[61] although there remains interest in using this agent in combination with immunotherapies (NCT02616185).

Bispecific Antibodies

Bispecific antibodies enable the simultaneous targeting of different epitopes by combining the specificities of two distinct antibodies. A common strategy has been to utilize heterodimers consisting of polypeptides of two antibodies (diabodies) or fusing two scFc fragments into tandem molecules (bispecific T-cell engagers [BiTEs]) to engage both a tumor cell surface–specific antigen, such as prostate-specific membrane antigen (PSMA), and CD3 on T cells.[62] Preclinical studies have demonstrated that these PSMA-CD3 molecules can effectively bring T cells into proximity with and lyse prostate cancer cells. Mechanistically, diabodies induce selective activation of T cells that are brought next to PSMA target cells via facilitation of TCR-CD3 clustering and CD3 conformational activation.[63] While diabodies have yet to demonstrate significant tumor regression in animal models, PSMA-CD3 BiTEs have produced PSA declines, inhibition of tumor formation, regression of established tumors, and significantly improved survival in mouse xenograft models.[64,65] This strategy has now been extended to dose-escalation phase I trials (NCT01723475, NCT02262910). Alternate targets, including human epidermal growth factor receptor 2 (HER2), which is overexpressed in 40% to 70% of prostate cancers, are also of interest; a phase I trial showed PSA declines in 3 of 7 CRPC patients, with one having > 50% reduction from baseline.[66] The accessory costimulatory molecule B7-H3 is aberrantly expressed in a variety of solid tumor malignancies, including prostate cancer, where it is associated with disease progression and poor outcomes. A B7-H3 × CD3 dual-affinity retargeting protein consisting of a diabody format stabilized by a C-terminal disulfide bridge is being evaluated for safety in a phase I dose-escalation study of 114 patients across a range of diseases, including prostate cancer (NCT02628535).

Adoptive Cell Transfer

Adoptive T-cell immunotherapy involves the isolation and subsequent ex vivo expansion and manipulation of autologous or allogeneic tumor-reactive lymphocytes that are then reinfused into the patient to target cancer cells. These T cells can be modified either by retroviral or lentiviral introduction of a novel TCR that is capable of recognizing cognate antigens presented on MHC-or by engineering them to express a chimeric antigen receptor (CAR) that recognizes a specific surface target on tumor cells.[67] While the efficacy of adoptive transfer of TILs was first demonstrated in melanoma nearly 3 decades ago,[68] progress in other solid tumors has been limited by significant off-target toxicities in early-phase clinical trials.[69,70] Such off-target toxicities, as well as resistance to TCR-redirected T cells due to human leukocyte antigen (HLA) subtype restriction, tumor downregulation of HLA, and low baseline affinities of endogenous TCRs, may be avoided by utilizing CAR T cells. Successful treatment of hematologic malignancies[71,72] with CAR T cells has ushered in a new era in cancer immunotherapy, and significant efforts are now underway to apply this technology to solid tumors, including prostate cancer. The cell membrane glycoproteins, PSMA, and prostate stem cell antigen (PSCA) have been the primary targets for CAR-T therapies in prostate cancer. PSMA is expressed across all stages of prostate cancer. The expression level is inversely correlated with androgen levels and plays an essential role in prostate cancer progression, making it an epitope for sensitive nuclear imaging and an attractive target for immunotherapy.[73] Preclinical studies demonstrated the cytotoxic potential of CAR T lymphocytes directed against PSMA and their ability to eliminate tumors in orthotopic murine models of prostate cancer.[74] In a phase I trial in 5 patients with mCRPC employing a first-generation PSMA CAR-T administered in conjunction with continuous low-dose IL-2 after cyclophosphamide preconditioning, 2 patients achieved 50% and 70% serum PSA declines and delays in PSA increases of up to 150 days.[75] A second-generation PSMA CAR-T was safely administered to 7 patients after preconditioning chemotherapy; 1 patient had stable disease for > 6 months and another had scans showing stable disease for > 16 months. A trial with this construct is currently active (NCT01140373).

A CAR created by the fusion of PSCA-specific single-chain antibody variable fragment, TCR-β2 constant region, and CD3ζ signaling domain activated transduced T cells and mediated in vitro lysis of PSCA-expressing cell lines.[76] A later study with a so-called third-generation anti-PSCA CAR, which incorporated CD28 and OX40 costimulatory domains, demonstrated in vitro antigen-specific activation, delayed tumor growth, and prolonged survival of nude mice but failed to fully eradicate the tumors.[77] This finding suggests the need for further optimization of CAR-T design or the addition of concurrent immune-stimulatory therapies to augment their cytotoxicity. To this end, recent efforts to optimize CAR-T selectivity demonstrated that use of the 4-1BB costimulatory domain and longer extracellular spacers enabled better persistence and robust antitumor activity of PSCA-CARs in xenograft prostate cancer models.[78] Further enhancement of adoptive T-cell therapy has been achieved in preclinical models by removal of local immunosuppressive circuits via introduction of a dominant negative TGF-β receptor II,[79,80] an approach now being investigated in a phase I trial (NCT0308920). Yet another intriguing combination approach is pairing targeted T-cell therapy with immune checkpoint inhibitors to enhance intratumoral trafficking of T cells and reverse CAR T-cell exhaustion in the TME.[81,82] Alternate targets have also been evaluated in the setting of adoptive CAR therapy for prostate cancer. CAR T cells targeting the cancer stem cell marker EpCAM inhibited tumor growth and metastasis formation and prolonged mouse survival.[83] Interestingly, significant antitumor activity was noted in orthotopic models with high EpCAM expression and in models derived from prostate lines with only a small population of cells expressing this marker, suggesting the possibility of effective targeting of cancer stem cells and the abrogation of tumor growth.

CAR-T constructs against novel antigenic targets, such as type I glycoprotein MUC1 or TCRs recognizing HLA-A2–restricted epitopes derived from a nuclear protein, which in turn is derived from an alternative reading frame of TCR gamma chain locus (TARP), have also demonstrated cytotoxic activity preclinically.[84] The challenge of increasing the specificity of CAR T cells in the absence of targets that are exclusively restricted to tumor has been approached by dual transduction of a CAR that provides suboptimal activation upon binding of one antigen and a chimeric costimulatory receptor that recognizes a second antigen. This strategy, which effectively creates an “and” logic circuit for T-cell activation, was successfully employed to target prostate tumor cells that expressed both PSMA and PSCA.[85]

NK cells are highly cytotoxic immune effectors that may provide key advantages over T cells as a platform for engineered CAR therapies.[86] Preclinical studies have demonstrated the feasibility of creating a CAR consisting of the NK signaling molecule DAP12 fused to anti-PSCA single-chain antibody fragments; results showed decreased tumor growth, improved median survival, and complete elimination of nearly one-third of tumors in nude mice inoculated with PSCA-expressing 293T cells.[87] The proteasome inhibitor bortezomib can enhance NK cell function while sensitizing tumor cells to cell-mediated cytotoxicity.[88] An immunomodulatory strategy combining bortezomib with adoptively transferred NK cells is now in early-phase trials (NCT720785).

Conclusion

Although the development of immunotherapies in prostate cancer has encountered significant hurdles in the form of relative resistance to checkpoint inhibition and ineffectiveness of various immunostimulatory strategies, there is still significant reason for optimism. Sipuleucel-T is just one example of the ability to generate an antitumor immune response against prostate cancer. In addition, the varied approaches previously tried have provided relevant insight into the nature of the immune response against this disease. We are now also learning that existing therapeutic strategies, including cytotoxic chemotherapy and antiandrogens, have immunostimulatory properties that can be leveraged to enhance future immunotherapy approaches. Ultimately, novel methods to reverse TME immunosuppression, to engineer targeted therapies against tumor cells and, in particular, to utilize combination strategies that manipulate multiple arms of the immune system will be the keys to improving the effectiveness of prostate cancer immunotherapy.

Financial Disclosure:Dr. Fong’s institution receives research funding from AbbVie, Bristol-Myers Squibb, Merck, and Roche/Genentech. Dr. Patel has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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