Dendritic cell vaccines for the treatment of prostate cancer

Urologic Oncology: Seminars and Original Investigations 26 (2008) 576 –580

Translational studies in urologic oncology

Dendritic cell vaccines for the treatment of prostate cancer Todd J. Lehrfeld, M.D., David I. Lee, M.D.* Department of Surgery, Division of Urology, Penn Presbyterian Medical Center, Philadelphia, PA 19194, USA

Abstract Advanced prostate cancer remains a disease with few options beyond palliation. Over the past few decades, our understanding of immunology has led to the development of novel therapies for the treatment of many malignancies, including prostate cancer. These generally aim to induce T-cell responses against tumor specific antigens to both reduce tumor mass and potentially avoid relapse. One promising technique is to use autologous dendritic cells, the most potent antigen presenting cell. These can be loaded ex vivo with a given antigen and subsequently injected back into the patient to stimulate the desired effect. Recent trials using these techniques have shown promise in extending survival in patients with prostate cancer. This review will discuss relevant biology behind dendritic cell therapy and highlight the key trials found in the literature. Published by Elsevier Inc. Keywords: Dendritic; Immunology; Prostate cancer; Metastatic; Advanced; Provenge; Immunotherapy

Introduction Prostate cancer is the leading cause of noncutaneous cancer in men in the United States, with 232,000 new diagnoses and 30,350 deaths in 2005 [1]. The advent of the PSA era has increased the number of cases diagnosed while creating a stage migration [2]. The standard treatments for localized disease include radical prostatectomy, radiotherapy, and cryosurgery. Over the past decade, expectant management has become an accepted treatment modality as well [3,4]. Unfortunately, in spite of current screening protocols, 30% to 40% of patients will fail local therapy as diagnosed by PSA increases [5]. One-third of these locally advanced patients will develop metastases in a median of 8 years, with these men having a 5-year median survival thereafter [6]. Furthermore, 15% of men will present with metastatic disease. Androgen deprivation therapy (ADT) with or without chemotherapy is standard treatment for metastatic disease. Eventually, most cancers lose hormone responsive status due to factors not currently completely understood. This period can take anywhere from weeks to years [7]. In addition, men are often placed on ADT prior to proven metastases secondary to small low level PSA recurrences, subjecting these men to the health consequences of castrate testosterone levels sometimes unnecessarily. There is cur* Corresponding author. Tel.: ⫹1-215-662-8699; fax: ⫹1-215-243-4649. E-mail address: [email protected] (D.I. Lee). 1078-1439/08/$ – see front matter Published by Elsevier Inc. doi:10.1016/j.urolonc.2007.12.002

rently no effective long-term treatment for androgen independent prostate cancer. Various chemotherapeutic protocols have been developed, with only taxotere based regiments demonstrating a modest, 6- to 7-month survival benefit compared with a placebo survival of 12 months [8,9]. Given the sheer number of patients this disease affects, developing alternative therapies for advanced prostate cancer is of prime concern.

The prostate as a target for immunotherapy The use of immunological therapy for metastatic disease is a relatively new modality. Interleukin-2 (IL-2) and lymphokine-activated killer cell administration for renal cell carcinoma, melanoma, and lymphoma were described in 1985 [10]. It has been established that immune modulation can protect the host from initiation of and, in some cases, decrease existent tumor burden [11]. To be a viable organ candidate for autoimmunotherapy, the target must be dispensable. Obviously, organs such as the brain or heart would not meet this criterion while the prostate would be ideal. The prostate gland has been extensively studied during inflammatory states such as prostatitis, where it has been found to be an active site of many immune mediators [12,13]. While the exact causes of these reactions are not fully understood, it is well established that this is largely

T.J. Lehrfeld, D.I. Lee / Urologic Oncology: Seminars and Original Investigations 26 (2008) 576 –580

T-cell mediated. It is also well known that cancer states correlate inversely with T-cell levels. Another factor making the prostate a favorable target is its association with unique immunoactive antigens. Those studied previously in an immunological context include prostate specific antigen (PSA) [14], prostatic acid phosphatase (PAP) [15], prostate specific membrane antigen (PSMA) [16], and prostate stem cell antigen (PSCA).

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then injected back to the patient as highly efficient and concentrated APCs, where they can invoke long-lasting tissue specific CD4⫹ and CD8⫹ responses and thereby decrease tumor burden. To this date, many prostate DC vaccines have been developed utilizing various epitopes, and have been used in Phases I, II, and III trials.

Vaccine development Tumor immunology The immune system is divided into the humoral and the cellular subdivisions. The predominant control of tumors involves the cellular (T-cell) arm, most notably via cytotoxic T-lymphocytes or CD8⫹’s (CTLs). It is of note that the CTL pathway is further propagated by the cytokines released by CD4⫹ activities (the humoral arm of the immune system), and are hence symbiotic branches. The recognition of a foreign antigen, or a tumor associated antigen (TAA), involves a three-fold process. First, an antigen-presenting cell (APC) processes and then presents TAA via major histocompatibility complexes (MHC). In general, exogenous peptides are processed as MHC-II and stimulate CD4 lymphocytes, whereas endogenous particles are processed as MHC-I and stimulate CTLs. Next, a given specific T-lymphocyte must recognize the appropriate APC and then attack the cell. Finally, a co-stimulatory signal between the CD28 on the CTL and B7 on the APC is essential for promoting antigen T-cell specific activation. Cancer is able to evade immunological destruction by a number of mechanisms. First, most TAAs are self-antigens providing self-tolerance. Second, tumors can down-regulate MHCs and alter cytokine concentrations (and hence immune response). Also, there is the presence of “Treg”, or regulatory CD4-CD25 T-cells [17], which can increase tumor response and growth in vivo [18]. The dendritic cell (DC) is the most efficient APC and thus is ideal for tumor therapy, as it has a high concentration of both MHCI and MHCII-antigen complexes as well as B7 co-stimulatory molecules. This greatly increases its chances for both correct T-cell location as well as stimulation [19]. Its efficacy has been proven both in vitro and in vivo [20]. DCs also have the unique properties that they can induce naïve CTL precursors to mature [21] and they can present exogenous peptides to CTLs. DCs originate in the bone marrow, and later migrate to the epithelium where they are exposed to various antigens. They subsequently mature and move to lymphoid tissue during an inflammatory state via exposure to toll like receptor (TLR) ligands, which are various “danger molecules” that further prime them for activity. They then interact with and activate CD4⫹ and CD8⫹ cell responses. It has been suggested that prostate cancer can inhibit development of DCs [22]. The purpose of vaccine therapy, then, is to propagate and antigen load DCs ex vivo. They are

Because of their low concentration in the blood, DCs must be grown ex vivo from hematopoietic precursors isolated from individual patients. The current method utilized is to collect peripheral blood and isolate monocytes as the precursors [23]. These are placed in serum free media for 5 to 7 days in the presence of cytokines GM-CSF and IL-4 to stimulate monocyte development into immature DCs; at this point they are primed for antigen capturing. Maturation continues in the presence of other biological agents such as TNF-␣, IL-6, and IL-1␤, and PGE-2 in addition to pulsing with the TAA of interest [24]. Most trials use solely cytokines for maturation prior to priming [25]; however, various TLR ligands have been studied and protocols for their use are being developed, as they may lead to more clinically efficient DCs as well as more standardized protocols.

Antigen loading In order to induce a specific response against the tumor, DCs must be loaded with TAAs efficiently during the maturation process. The desired result is expression of the DCs with both MHC-I and MHC-II derived TAA product [26]. The most common ex vivo technique of this is to pulse DCs with TAAs presented by the desired MHC complex. A popular version utilized is to transfect DCs with the mRNA of the chosen TAA, enabling the cell’s own genetic machinery to produce the protein, enhancing the MHC-I pathway [27]. The choice of TAAs are naturally tumor specific. In prostate cancer trials, PSA, PSMA, PAP, and PSCA have all been used. Additionally, molecules such as telomerase reverse transcriptase (TERT), survivin, and Her-2/neu are activated in most cancers, and have been used as well in various vaccines [28 –30].

Specific trials The first series of Phase I-II trials of DC therapy were done using PSMA, a glycoprotein found in both malignant and benign prostate cells, as well as other tissues [31]. DCs were loaded with HLA-A2 restricted PSMA derived proteins and were administered intravenously to patients with hormone-refractory prostate cancer [32–36]. There were 7 partial responders out of 51 in the Phase I trial, and 9 partial

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T.J. Lehrfeld, D.I. Lee / Urologic Oncology: Seminars and Original Investigations 26 (2008) 576 –580

responders out of 33 in the Phase II trial. Response was based on serum PSA change, bone scan, and Prostascint scan. Of note, 3 of the latter responders were HLA-A2 negative, leading one to infer that this treatment may be activating innate immunity in addition to CTLs specific to the given HLA class. A randomized, double-blinded Phase III placebo-controlled study is currently being planned. PSA, a serine protease, is widely used in trials as it is found in few tissues outside of prostate, and is conserved in even the most undifferentiated of tumors [37,38]. It is released from tissue into the peripheral blood circulation, and can easily be detected, making it an ideal marker and target. Heiser et al. vaccinated 13 patients with PSA mRNA transfected autologous DCs to test safety and proof of concept. In addition to no dose-limiting toxicity or adverse effects, 6 of these patients demonstrated a significant PSA velocity decrease. However, these results were not clinically significant [39,40]. Recombinant PSA protein has also been used to pulse DCs. In one series, 24 patients received 9 total injections. No patient had a clinically relevant response, but 11 demonstrated a decrease in PSA between injections [41]. Summing up all current series based on PSA DC vaccines, 49 out of 99 patients had an immune response, but unfortunately none were clinically significant based on survival data [40 – 46]. In what is perhaps a more generalizable cancer study, DCs transfected with mRNA hTERT was administered to 20 patients with metastatic prostate cancer. Nine of these patients also received lysosome-associated membrane protein-1 (LAMP), which promotes the exogenous MHCII pathway, and hence CD4⫹ cell development. Nineteen of 20 subjects had a measurable increase in hTERT-specific CTLs. While both groups had increased CD4⫹ cells, the one which received LAMP had a significantly higher response, as expected. This group also had more effective CTLs; this is likely because CD4⫹ cells are essential for CTL development. A small improvement was noted in PSA doubling time and transient serum PSA clearance in several patients [47].

Provenge A currently studied vaccine, sipuleucel-T (APC8015, Provenge), consists of autologous DCs pulsed ex vivo with the fusion protein PAP-GM-CSF and consequently re-infused. PAP is expressed by 95% of human prostate cells as well as in the testicles, brain, liver, heart, and spleen [48,49]. GM-CSF is a cytokine that stimulates DC function markedly. An initial Phase I trial demonstrated that all patients developed immune responses to the fusion protein, while 38% responded to the PAP component alone [50]. A later trial demonstrated 100% immune response to the individual components as well in 31 patients, likely due to a different processing technique. The vaccine was well toler-

ated in all trials thus far, with fever being the main side effect demonstrated in 15% of patients in one trial [50]. Phase II trials performed concurrently demonstrated greater than 50% reduction in PSA in 3 out of 12 patients over the course of the trial [50 –52]. Time to progression of disease was correlated with the amount of immune response and with the dose of vaccine received. In a landmark Phase II trial, Burch et al. demonstrated 1 patient with a complete response, in which his PSA dropped from 221 ng/mL to undetectable levels, and pelvic and retroperitoneal lymphadenopathy resolved on radiography. The patient remained clinically disease free for 4 years [52]. These early studies demonstrated sipuleucel-T to be safe, effective in stimulating an immune response towards PAP, and hence worthy of Phase III trials. A multi-institutional Phase III study was performed with 127 patients with radiologic evidence of metastasis. This did not demonstrate a statistically significant change in the progression of disease based on worsening radiographic findings and pain (P ⫽ 0.052). However, mean survival time increased from 21.4 months in the placebo group to 25.9 months in the sipuleucel-T group, giving it a 4.5-month mean survival advantage (P ⫽ 0.01). Furthermore, 34% of study patients were alive at 36 months compared to 11% of those who received placebo [53,54]. For patients with low grade (Gleason ⱕ 7) disease, there was also a small increase in time to progression (16.1 weeks vs. 9.1 weeks, P ⬍ 0.001). Bioassays demonstrated an 8-fold increase in T-cell stimulation at 8 weeks (P ⬍ 0.001). This is the only placebo controlled prostate cancer study to date demonstrating a survival advantage with an immunotherapeutic modality. A currently ongoing trial, P-11, is a double-blind, multicenter, randomized study with 176 patients who have undergone radical prostatectomy with subsequent rising PSA levels and have been started on ADT. Early results are demonstrating a slower PSA rise in the treatment group (30% to 48% less) [55].

Conclusions Metastatic prostate cancer is a difficult condition to treat as no therapies currently improve quality of life or life span significantly beyond placebo. A revolution in treatment approach is necessary. The technological improvements over the past 2 decades have led to the dawn of translational medicine where molecular biology may affect clinical medicine. A deeper understanding of immunology, a field that conceptually lends itself to the treatment of prostate cancer, could enable up-regulation of one’s immune system to become more efficient in killing metastatic cells by priming the patient’s own highly efficient T-cells to recognize them as “non-self” on a molecular level. Interestingly enough, this may be one of the mechanisms of ADT, as the hormone-deficient state has been associated with increased T-cell numbers and activation. DCs are the most effective

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cells for stimulating such reactions, and have been a prime target in trials for many metastatic cancers including the prostate. In its first decade, trials have essentially demonstrated proof of concept, and treatments have been shown to be safe with few side effects. Newer cell targets such as PSCA, which is highly prostate specific, are currently being considered for trials. In addition, Provenge has demonstrated to be promising in Phases II and III trials; while it has not shown, thus far, a statistically increased change in disease progression, it is associated with a slightly increased survival time, and further studies may be powered to show greater results. As they rely on the host’s intact immune system, treatments such as chemotherapy may decrease immunotherapy effectiveness. Late stage cancer patients also have significantly compromised immune responses from the disease process itself. Once consideration for immune therapy protocol is given, patients have already been ravaged by their disease and sometimes treatments and are unable to undergo DC injections. Future trials will need to be performed comparing newer treatments with those more established chemotherapy regimens. With these issues in focus, dendritic cell therapy seems to have significant promise as a treatment modality where no effective treatment previously existed.

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