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Abstract

Prostate cancer (PCa) is the second leading cause of cancer-causing death in the United States. As the most common malignancy in men, it is pertinent to explore whether novel immunotherapies may improve the quality of life and overall survival (OS) of patient populations. This systematic review and post hoc analysis curates a patient-by-patient pool of evidence adhering to PRISMA Statement 2020 guidelines. In total, 24 patients were analyzed for treatment history and associated variables including prostate-specific antigen (PSA) levels at diagnosis and post-treatment, Gleason score, secondary tumor locations, success/failure of therapy, and post-immunotherapy outcomes including OS. In total, 10 types of immunotherapies were identified with Pembrolizumab (among 8 patients) followed by IMM-101 (among 6 patients) being the most commonly administered. The mean OS for all patients was 27.8 months (24 patients) with the relatively highest mean OS reported with IMM-101 (56 months) followed by tumor-infiltrating lymphocytes (30 months). This research article provides critical insights into the evolving landscape of immunotherapies being tested for PCa and addresses gaps in oncological research to advance the understanding of PCa.

Keywords

prostate cancer immunotherapy biologics precision medicine

Introduction

Prostate cancer (PCa) is the second leading cause of cancer-related death in the United States and the most common malignancy in men (Sayegh et al., 2022). In men with a moderate risk of prostate cancer or clinically localized disease, surgical or radiation therapy and active surveillance is the recommended treatment option (Mottet et al., 2021; Zelefsky et al., 2019). However, patients with high-risk diseases have a higher risk and rate of failure post external radiation radiotherapy or radical surgery (Olivas & Price, 2021). This may be due to occult metastasis at the time of diagnosis (Bax et al., 2018; Bjurlin et al., 2015; Kasivisvanathan et al., 2018). Local control of PCa has a large impact on the subsequent risk of cancer-related death and distant metastasis (Surasi et al., 2020). Typically, the natural course of PCa is variable and slow-growing (Cooperberg et al., 2010). When metastasis occurs throughout the body mainly in the lymph nodes, bones, and lungs, cancer becomes aggressive (Bubendorf et al., 2000). As PCa is largely regulated by androgen receptors that bind to ligands and trigger molecular reactions forming active transcription complexes, these lead to downstream gene expression, reduce incorrect gene transcription, lead to cancer cell death, and suppress the tumor (Crawford et al., 2019). For metastatic or locally advanced PCa, androgen deprivation therapy (ADT) through orchiectomy or chemical castration with paclitaxel-based or anti-androgen chemotherapy is the most commonly used treatment, as reported by Yamada and Beltran (2021); the fundamental approach to the treatment of PCa is ADT, either pharmaceutical or surgical for castration-sensitive diseases. ADT comprises anti-androgens, gonadotropin-releasing hormone analogs, or a combination used for long-term leads to maximum levels of androgen blockage (Dong et al., 2022). These measures suppress prostate-specific antigen (PSA) levels by 80% to 90% and lead to objective responses in bone and soft-tissue metastasis (Fujita & Nonomura, 2019). However, ADT is associated with diabetes, sexual dysfunction, cardiovascular disease, decreased mineral bone density, and cognitive dysfunction.

Despite ADT leading to maintained testosterone serum levels at a low range, PCa cells enter a dormant capacity, survive, and eventually relapse in nearly all patients who undergo disease progression within 8 to 24 months of commencing treatment (Katzenwadel & Wolf, 2015; Lokeshwar et al., 2021). This leads to a state of castration-resistant prostate cancer (CRPC), which is both incurable and inevitable (Yu & Aragon-Ching, 2022). At the CRPC stage, genes including androgen receptor (AR), TP53, RB1, PTEN, and DNA damage repair (DDR) are in a mutated state (Mateo et al., 2020). With the development of molecular mechanisms, PCa cells proliferate and survive even without the absence of testosterone (Li et al., 2021; Santer et al., 2015). Androgen deprivation leads to neuroendocrine transdifferentiation, epithelial–mesenchymal transition (EMT), and stem cell-like gene expression programming that forms treatment-refractory phenotypes of the metastatic tumor (Dicken et al., 2019). Conventional therapy modalities include chemotherapeutic approaches with drugs such as docetaxel, paclitaxel, and cyclophosphamide (Petrylak et al., 2004; Raghavan et al., 1993). These are limited approaches given a high level of drug resistance, short circulation time, and the low bioavailability of drugs along with side effects specific to chemotherapy that impact the quality of life among men (Chabner & Roberts, 2005; Xu et al., 2015). As of 2023, multiple novel immunotherapies are being tested in patient populations, under controlled environments, on a compassionate use basis, or as a precision medicine-guided intervention. This systematic review and post hoc analysis aims to curate a pool of patient-by-patient currently published evidence (i.e., January, 2017-January, 2023) to ascertain whether immunotherapy, either as an adjuvant or monotherapy, improves outcomes in patients with PCa.

Method

Search Strategy and Study Selection

As per the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 statement, a thorough systematic literature search was conducted between January 1, 2017 and January 25, 2023. The rationale behind the date restriction was to include relevant, non-defunct clinical data, latest evidence, and key breakthroughs in this systematic review and post hoc analysis; this was determined post-preliminary search of relevant articles and idea validation (Tawfik et al., 2019). The following keywords were applied, applying the Boolean logic (and/or): prostate, cancer, immunotherapy, case, report. An a priori approach was generated to include clinical reports and ensure that the outcome measures were listed systematically for inclusion in our study. The protocol of this systematic review and post hoc analysis is registered with OSF: osf.io/sqyab. All methods were carried out in accordance with relevant guidelines and regulations (Declaration of Helsinki). An ethical approval exempt status was granted considering the publicly accessible documents utilized as data sources in this study. The PRISMA flowchart is depicted in Figure 1. The PRISMA checklist is attached in the Supplementary Materials.

Figure 1.

PRISMA Flowchart Depicting the Study Selection Process (Page et al., 2021).

For this analysis, only case studies with individual patient data were included, whereas cohorts, clinical trials, systematic reviews, and meta-analyses were excluded. The following three databases were searched: PubMed/MEDLINE, Cochrane, and CINAHL Plus. To ensure that all relevant studies were included, we screened the reference lists of included studies (umbrella methodology).

The PICO framework was classified as patients with prostate cancer (local or metastatic), with castration sensitive or resistant disease (P); they were intervened with immunotherapy (I); without any comparators (C); post-immunotherapy outcomes of overall survival (OS), progression-free survival and radiographic findings were enlisted (O).

Eligibility Criteria

Male patients of any age group with PCa (local or advanced) who are receiving immunotherapy (only) or as a combined approach (multimodal) at any time point of treatment. The patients were required to receive immunotherapeutic treatment, which is a biological therapy that uses substances made from living organisms to treat PCa. Different types of immunotherapies could comprise the following:

Immune checkpoint inhibitors (ICIs): Drugs that block immune checkpoints to enhance the immune response to PCa.

T-cell transfer therapy: Treatment that boosts the natural ability of T cells to respond to PCa that uses immune cells extracted from the tumor. It may also be referred to as adoptive cell therapy, immune cell therapy, or adoptive immunotherapy.

Monoclonal antibodies: Immune systems proteins created in the laboratory that are designed to bind to specific targets on PCa cells. They may also be referred to as therapeutic antibodies.

Vaccines: These work by boosting the immune system’s response to PCa cells and are different from disease prevention.

Immune system modulators: These enhance the body’s immune response against PCa and affect specific parts of the immune system as compared to general immune system responses.

Data Extraction and Synthesis

The following data were extracted from the included studies in two parts: (a) author, year, journal, patient count, immunotherapy administered, role in current practice, clinical approval status; (b) age (in years), PSA levels, Gleason score, secondary tumor location(s), treatment timelines, post-immunotherapy outcomes. All data were input into a shared spreadsheet, which was extracted independently by four authors for analysis and cumulative result interpretation ( M.U.A., U.F., M.S. and Z.S. ). All discrepancies were resolved by two authors ( A.S. and Z.S. ) and a consensus was reached. The findings were thereby tabulated.

Data Analysis

The fourth and sixth authors ( A.S. and Z.S. ) extracted all nominal and ordinal data for analysis using Statistical Package for Social Sciences (SPSS v25). Descriptive trends (the number of participants, percentage) were estimated for the following variables: age, Gleason score, immunotherapies administered, and mortality (dead vs. alive). For continuous variables, mean and standard deviation (SD) were also computed. The post hoc analysis comprised quantitative measures for estimating the mean OS. A box plot was also generated with measures of median OS depicting the outcome of interest (median OS).

Results

Summary of Findings

A total of 16 case reports were included in this systematic review pooling in 24 patients. In line with the key outcome of this study, we presented PSA findings at diagnosis and post-treatment, the Gleason score on diagnosis, secondary tumor locations (if any), treatment timelines to curate a bird-view of approaches being used among the included patients that provided success or failure, and post-immunotherapy outcomes. The characteristics of the included studies are listed in Table 1. Synthesized findings of the patient population and clinical outcomes are detailed in Table 2.

Table 1.

Characteristics of the Included Studies.

No.	Author, year	Journal	N	Immunotherapies administered	Role in clinical practice	Clinical approval status
1	Dalgleish & Liu, 2022	Oncology Letters	6	IMM-101^a	IMM-101: tested as a novel immune-therapy as a general adjunct to chemotherapy	Phase I and Phase II in the clinical pathway
2	Idossa et al., 2022	Frontiers in Oncology	2	Pembrolizumab	Pembrolizumab: tested in docetaxel-refractory mCRPC but extrapolation of data in patients with HIV is limited	FDA approved (2018) for MSI high or mismatch repair-deficient PCa; also for high tumor mutational burden (>10 mutations per megabase) (2020)
3	Ravindranathan et al., 2021	Case reports in Oncology	2	Pembrolizumab	Pembrolizumab: used to target antibodies in the programmed cell death protein, PD-1 pathway	FDA-approved for all solid tumors (2014) with MSI or dMMR regardless of primary origin
4	Han et al., 2020	Therapeutic Advances in Medical Oncology	1	Pembrolizumab	Pembrolizumab: when combined with RT, it may re-invigorate the initial response to anti-PD-1 therapy and enhance durability	FDA-approved for all solid tumors (2014) with MSI or dMMR regardless of primary origin
5	Lainez-Nuez et al., 2020	Journal of Investigational Allergology and Clinical Immunology	1	Pembrolizumab	Pembrolizumab: given alongside Abiraterone Acetate to improve overall survival and overcome PCa tx failure	FDA-approved for all solid tumors (2014) with MSI or dMMR regardless of primary origin
6	Sena et al., 2021	Cold Spring Harbor Molecular Case Studies	1	Pembrolizumab	Pembrolizumab: used as a central therapy for PCa with parenchymal brain metastases	FDA-approved for all solid tumors (2014) with MSI or dMMR regardless of primary origin
7	Zhu et al., 2022	OncoTargets and Therapy	1	PD-1 inhibitor (unspecified)	PD-1 inhibitor: monotherapy with PD-1 inhibitors has rarely demonstrated dramatic response rates in mCRPC; its role is being tested in Phase I-III clinical trials	FDA has approved (Since 2006) only 3 PD-1 inhibitors (Pembrolizumab, Nivolumab, and Cemiplimab); None have been approved for PCa and are either used under controlled testing or compassionate use
8	Basnet et al., 2017	Clinical Genitourinary Cancer	1	Nivolumab	Nivolumab: used as a fifth-line agent post being refractory to 3 chemotherapies and Enzalutamide	FDA approved Nivolumab (2022) for only early-stage non-small cell lung cancer; in Phase II/III testing for PCa
9	Monge et al., 2018	Journal of ImmunoTherapy of Cancer	1	Nivolumab and PROSTVAC	Nivolumab and PROSTVAC: Therapeutic cancer vaccines and ICIs together were tested to induce antitumor activities through immunogenic intensification	FDA approved Nivolumab (2022) for only early-stage non-small cell lung cancer; in Phase II/III testing for PCa; Whereas, PROSTAC is not FDA approved and is being tested in Phase I-III clinical trials for PCa
10	Sharan et al., 2020	Medicine	1	Personalized Dendritic Cell Immunotherapy (APCEDEN)	APCEDEN: tested as a combination therapy in patients with advanced PCa (i.e., skeletal metastases)	Cell-based vaccines (Sipuleucel-T) have been approved by the U.S. FDA (2010); APCEDEN was approved by the Indian FDA (2017)
11	Kumar et al., 2019	Future Science	1	Personalized Dendritic Cell Immunotherapy (APCEDEN)	APCEDEN: administered in combination with systematic chemotherapy (i.e., Mitoxantrone) to enhance antitumor immunity	Cell-based vaccines (Sipuleucel-T) have been approved by the U.S. FDA (2010); APCEDEN was approved by the Indian FDA (2017)
12	Van Bos et al., 2020	Journal of Medical Case Reports	1	Atezolizumab	Atezolizumab: used as a maintenance add-on therapy along with chemotherapy to manage SCCP	FDA approved Atezolizumab (2021) for NSCLC/TNBC/etc. but it is being tested in Phase I-III clinical trials for PCa
13	Cabel et al., 2017	Journal for ImmunoTherapy of Cancer	2	Ipilimumab	Ipilimumab: patients were enrolled in two trials (CA184-043 and CA184-095) and used the tx as monotherapy post multiple-previous interventions	Ipilimumab is in pre-clinical and clinical testing for different PCa subtypes
14	Karbach et al., 2023	Journal for ImmunoTherapy of Cancer	1	Pembrolizumab and Tumor Infiltrating Lymphocytes (TIL)	Pembrolizumab: given as a co-therapy before tumor-infiltrating lymphocyte (TIL) infusion as checkpoint blockade	FDA-approved for all solid tumors (2014) with MSI or dMMR regardless of primary origin
15	Shi et al., 2018	Medicine	1	Cytotoxic T lymphocyte (CTL) immunotherapy [TIL]	TIL: An autologous cellular immune therapy that is used for treating patients with malignant tumors, although its role in PCa is still being understood	Not FDA approved insofar for PCa, but alloreactive CTL immunotherapy is being posited as a promising alternative therapy for tx
16	Zhang et al., 2019	Clinical Genitourinary Cancer	1	Sipuleucel-T	Sipuleucel-T: used as monotherapy to contain disease progression in mCRPC	FDA approved (2010) the autologous cellular immunotherapy for asymptomatic or minimally symptomatic mCRPC

Note. dMMR = DNA mismatch repair; CTL = Cytotoxic T lymphocyte; TIL = tumor-infiltrating lymphocyte; FDA, Food and Drug Administration; SCCP = Pure Small Cell Carcinoma of the Prostate.

IMM-101 is an immunotherapeutic agent in clinical development as an adjunctive treatment in cancer. It comprises heat-killed whole-cell Mycobacterium obuense, which is being developed for testing and patient use.

Table 2.

Patient Populations and Clinical Outcomes.

Author, year	Age (in years)	PSA levels	Gleason score	Secondary tumor location(s)	Treatment timelines	Post-immunotherapy outcomes
Dalgleish & Liu, 2022	61	4.2 → 1.4 (Year 1)	NR	Bone metastatic lesions in the pelvis; Lymph nodes; Seminal vesicle	Year 1: Bicalutamide; Year 2: Goserelin, M. vaccae (clinical trial), zoledronic acid; Year 3: Radiotherapy; Year 5: Hormone-tx stoppage; Year 8: IMM-101 and Zoledronic acid; Year 9: Cyberknife and resumption of CAB	Small rise in PSA levels while remaining on IMM-101 for metastases including bone deposits leading to recommencement of CAB with otherwise well general health
	56	6.0 (Screening)	3+4 bilaterally in 6/10 cores	Seminal vesicle	Over 6 Years: Radical prostatectomy, radiotherapy (66 Gy in 33 fractions) without ADT, IMM-101, Aspirin, Vitamin D3 correction/Anti-inflammatory agents	With locally advanced PCa, IMM-101 was begun to avoid CAB therapy (due to side effects); the PSA doubling time was slowed with no evidence of disease progression and good quality of life for six years
	69	Elevated (Value NR)	4+3	Bilateral peri-prostate invasion; Para-aortic nodes	Year 1: Radical prostatectomy, IMRT with 6-month endocrine therapy; Year 3: IMM-101, Vitamin D-3 correction, Bromelain; Year 7: CAB therapy	With elevated PSA levels and prostate problems, radical prostatectomy was conducted followed by IMRT; IMM-101 addition helped in avoiding CAB side-effects for 5 years
	61	Elevated (Value NR)	4+5	Extra-prostatic extensions	Over 3 Years followed through Year 5: Radical Prostatectomy, followed by hormone treatment & IMRT; Commenced on IMM-101 with LDN and Vitamin D3 correction; Begun on Docetaxel post new node development (IMM-101 and LDN ongoing)	IMM-101 and LDN alone led to 3-year stable disease without hormone tx; complete response to chemotherapy for lymph node progression was seen with 5-year stability of PCa
	61	Peak PSA rose to 40 after 2 years of clinical stability; reduced to 1.5 with abiraterone	4+4	Multiple bone metastases	Initial tx was Goserelin; Bicalutamide led to no response; Commenced on IMM-101 (53% PSA fall); LDN added; Response to Abiraterone seen (PSA 40->1.5); Radium 223 (6 cycles) and local radiotherapy; Further response to Docetaxel and Cabazitaxel	With aggressive PCa, LDN partnered with IMM-101 led to clinically stable disease for two years; 9-year survival was seen with multiple conventional interventions (radio-, chemotherapy)
	62	Elevated (Value NR)	3+4+7	Seminal vesicle; Retroperitoneal lymph nodes	Over 5 Years: Radical prostatectomy followed by radiotherapy and Biclutamide (PSA doubling time = 9 months); Vitamin D3 levels corrected and Aspirin/Bromelain added; IMM-101 added in Year 5 coupled with LDN (quick PSA level reduction)	No hormone tx was administered, where IMM-101 and LDN led to PSA breakthrough with MRI/PET scans stability before developing severe HF and abdominal malignancy not related to PCa
Idossa et al., 2022	52^a	81 (Screening); 30 (Nadir)	NR	NR	Commenced on intermittent ADT (60 months), followed by ADT & Dutastaride (60 months); begun on Provenge (2.25 months), Nilutamide (12 months), Abiraterone (42 months), Enzalutamide (3 months), Radium 223 (6 months) and finally Docetaxel (6 months)	Partial response was seen for 31 months post-immunotherapy and the patient remained on tx
Idossa et al., 2022	62^b	846 (Screening); 337 (Nadir)	NR	Metastatic (locations NR)	Begin with ADT (40 months), then on Abiraterone (8 months), followed by Enzalutamide (3 months), Docetaxel (2.25 months), Cabazitaxel (4.5 months), Radium 223 (6 months), and finally Rucaparib (1 month)	Stable radiographic findings were seen for 14 months; new brain metastasis, clinical decline, and death were reported 1 month after the last dose of pembrolizumab
Ravindranathan et al., 2021	51	353 ng/mL (Diagnosis); <0.01 ng/dL (Post-tx, Lowest)	5 + 5	Left renal pelvis; Proximal left ureter; Interface between the prostate and left posterior aspect of the urinary bladder	Initially received Bicalutamide then Leuprolide injections 3-monthly combined with Docetaxel (3 cycles); started on Prednisone and Abiraterone due to PSA rising; Enzalutamide commenced (PSA decreased); then underwent 6 cycles of Carboplatin and Etoposide; Pembrolizumab was commenced 3-weekly (total of 12 cycles, PSA<0.01 ng/dL)	Post 12 cycles of Pembrolizumab (200 mg, IV every 3 weeks), PSA levels were undetectable with MRI showing no residual mass in the abdomen and pelvis; liquid biopsy analysis after 5 cycles of pembrolizumab showed clearance of somatic alterations and MSI-H status
Ravindranathan et al., 2021	81	11 ng/mL (Diagnosis); 0.11 ng/mL (post-tx, Lowest)	4 + 4	Left iliac spine; Right posterior sixth rib	Begun on leuprolide injections and prostate-targeted proton therapy; Enzalutamide was commenced 2.5 Years later due to bony metastases; 2 Years later, Prednisone and Abiraterone was commenced with Sipuleucel-T (discontinued due to allergic reactions); Docetaxel (7 cycles) and Radium-223 (5-cycles later), MSI-H status was detected where Pembrolizumab was administered (5 cycles)	PSA level post-5 cycles of pembrolizumab was 0.11 ng/mL; repeat liquid biopsy analysis showed a significant reduction in somatic variant allele frequency (15% to 0.5%) along with clearance of MSI-H status
Han et al., 2020	75	20.4 ng/mL (Diagnosis); Undetectable (Post tx, 6 cycles)	5+5	Bladder lumen; Seminal vesicles; Acetabular and pelvic sidewall	30 Months: Initial tx was Abiraterone, Leuprolide, and Prednisone; Systemic Carboplatin and Docetaxel were given worsening dx; SBRT (3800 cGy reduced PSA >90%, 4 cycles); Compassionate use Pembrolizumab was begun with palliative radiation (external beam RT)	With Pembrolizumab (2 cycles) and 1920 cGy of RT combined, exceptional response was observed; the patient continues on Pembrolizumab monotherapy with no symptoms of colorectal and bladder toxicity
Lainez-Nuez et al., 2020	47	NR	8	Lymph nodes and Bone	Year 1-2: Oral Bicalutamide, IV Leuporelin Acetate, Docetaxel (6 cycles); Year 3: Abiraterone Acetate 1,000 mg a day with Oral Prednisone (10 mg a day), with IV Pembrolizumab (200 mg, 3 weekly)	While Abiraterone Acetate combined with steroid usage led to delayed systemic reactions, Pembrolizumab was continued as first-line with the patient developing no signs of hypersensitivity (immediate or delayed)
Sena et al., 2021	60	15.3 ng/mL (Diagnosis); PSA decline of 79% (Post tx)	4+5	Several parenchymal brain lesions	External-beam RT with ADT (1.5 Years); Craniotomy, Stereotactic RT, and Enzalutamide; then begun on Pembrolizumab (200 mg, 3 weekly); Initiated on Dexamethasone, Repeat Craniotomy, and brain-directed RT; Continued on Pembrolizumab (6 months); Initiated on Docetaxel chemotherapy (3 months); Comfort Care (several weeks)	On first commencing Pembrolizumab, PSA declined by 79% with partial radiographic response to metastatic lymphadenopathy; post the third infusion, the patient was diagnosed with brain metastasis; post various measures, the patient was continued on Pembrolizumab for 6 months until the PSA progressed and metastatic lymphadenopathy worsened; one-year post initial diagnosis of brain metastasis, he died
Zhu et al., 2022	55^c	16.56 ng/mL (Diagnosis); 0.26 ng/mL (Nadir, post 4 cycles of platinum-based chemotherapy)	8	Lung, Thoracic vertebra, Neck, and Mediastinum	3.75 Years: Year 1: Underwent laparoscopic RP, then begun on 66 Gy adjuvant RT with ADT; Year 2: First-line Docetaxel (low-yield), then switched to Cis-Platinum chemotherapy (due to CDK12 mutation, 4 cycles); Year 3: Switched to Abiraterone, and later on to literature-support PD-1 inhibitor	In the last year of survival, the patient was administered a PD-1 inhibitor (unspecified), which did not alter his liquid biopsy genetic test, and the patient later died due to cerebral infarction
Basnet et al., 2017	65^d	77.5 ng/mL (Post-dx); <0.1 (Post-tx, 15 cycles)	5+5	None	Started on ADT and Bicalutamide daily, with anticoagulation; then on Docetaxel (3 cycles); Begun on Enzalutamide (3 cycles), transitioned to Cabazitaxel & Carboplatin (6 cycles); Finally started on Nivolumab on a compassionate basis (19 cycles)	PSA levels post 19 cycles of Nivolumab (employed as 5th-line tx) led to undetectable PSA levels (<0.01), with pelvic mass reduction from 10 cm × 5.7 cm × 8.7 cm to 7.9 cm × 1.7 cm
Monge et al., 2018	79	NR	NR	Bone and lymph nodes	A full timeline was not provided, however, the patient was enrolled in a Nivolumab (1 mg/kg) and PROSTVAC (every 2 weeks) combined clinical trial for 8 weeks	Post-anti-PD-1 and vector-based vaccine therapy (8 weeks), the patient developed myocarditis (hx of atrial fibrillation), leading to Nivolumab discontinuation and PROSTVAC continuation for 3 more months; no residual cardiac damage was observed
Sharan et al., 2020	58	200 ng/mL (Screening); 0.4 ng/mL (Lowest, Year 3)	8	Paraaortic, aortocaval, and bilateral external iliac lymph nodes	Year 1: Chemotherapy (Zytiga and Lupron) with hormone tx; Year 3: Dendritic Cell Immunotherapy (APCEDEN, 6 doses), Year 4: APCEDEN (6 booster shots)	Post APCEDEN (6 doses), remission was observed (PSMA avidity by 50% reduction in SUV max); post 6 booster doses, prostate was normal in size with non-PSMA expression lesions; blood PSA and testosterone levels were concordant
Kumar et al., 2019	63	82.17 ng/mL (Diagnosis); 8 ng/mL (Lowest, post immunotherapy, 6 doses)	8	Iliac and para-aortic, mediastinal, supraclavicular nodes; skeletal lesions (D4-D9 and C3, C6 vertebral bodies)	7 Years: RT (7740 cGy in 43 fractions), Year 1-2; Chemotherapy (Docetaxel, 6 cycles) with 9 cycles of abiraterone, Years 3–4; Palliative RT (30 Gy, 10 cycles). Year 4; Chemotherapy (Docetazel, 6 cycles), Year 4; APCEDEN, Years 5–6	Post APCEDEN (6 doses), reduction in NLR and PLR were observed with the lowest PSA levels noted at 8 ng/mL; the patient also received mitoxantrone, which in combination led to improved cell-mediated immunity as lymphocytes percentage increased
Bos, 2020	73	8.59 ng/mL (Diagnosis); 0.17 ng/mL (Nadir)	3+3	None	Year 1: Low-dose-rate brachytherapy was performed; Year 9: Chemotherapy was commenced (Carboplatin and Etoposide) plus Atezolizumab for 6 cycles	Post 3 cycles of Atezolizumab, partial response was witnessed that was maintained for 6 cycles, but the patient already developed advanced disease by the second cycle
Cabel et al., 2017	51^e	225 ng/mL (Diagnosis); <0.05 ng/mL (Post tx, 6 weeks)	8	Multiple synchronous bones; Lymph nodes	5 Years: Begun on Goserelin, followed by ADT; post resistance, received chemotherapy (Docetaxel-6 cycles and Prednisone); bone pain required oxycodone administration; single fraction RT (8 Gy) delivered to T8-T11; then begun on Ipilimumab (for 3 Years total) and stopped	After around 3 years of Ipilimumab therapy, the patient was still asymptomatic with complete morphologic/biologic response at 64 months, however, along the course he experienced grade 2 rash/grade 1 diarrhea
Cabel et al., 2017	49	44.8 ng/mL (Diagnosis); <0.01 ng/mL (Post tx, 13 weeks)	8	Bone; Lymph nodes	~19 Years: Prostatectomy and lymph node dissection (Year 1)- adjuvant RT (45 Gy) and brachytherapy (8 Gy); Year 2: intermittent ADT for seven years; Year 13: Ipilimumab 3-weekly then maintained every 3 months for three years	Post initial Ipilumumab administration PSA rose from 70 to 81 ng/mL (third week) and declined regularly thereafter reaching <0.01 ng/mL levels at the third year of tx
Karbach et al., 2023	70s	33 ng/mL (Commencement of tx); <0.01ng/mL (Post tx, 3 cycles of TIL, 4 cycles of Pembrolizumab)	4+5	Urethra, para-urethral soft tissue, penis root, and lymph nodes	Year 1: Radical prostatectomy, RT to single bone metastasis (67 Gy), various hormonal treatments; Year 14: TIL infusion (3 sessions) along with Pembrolizumab (4 doses) over three years	TIL administration at relatively low cell numbers when combined with Pembrolizumab led to complete tumor regression led to remission for 3.5 years and counting
Shi et al., 2018	82	54.54 ng/mL (Diagnosis); <0.01 mg/mL (Post tx, 28 cycles of alloreactive CTL)	NR	Multiple bones, Lungs, Liver, Brain	Initially commenced on RT and chemotherapy (poor response); then begun on immune therapy of alloreactive CITL (28 cycles, PSA 2.63 to <0.01 ng/mL); Immunotherapy stopped due to expensive cost and lack of proper blood supply	Post alloreactive CTL therapy, the PSA reached undetectable levels, with the patient remaining stable for 2 years; no metastatic lesions were detected in other organs, including the lung, liver, and brain, despite being initially diagnosed with metastatic dx
Zhang et al., 2019	71	50.36 ng/mL (post-RP and salvage RT); 0.418 (post 3 cycles of immunotherapy)	3+4	Lungs, mediastinal, and supraclavicular lymph nodes	Initially commenced on RT and chemotherapy (poor response); then begun on immune therapy of alloreactive CITL (28 cycles, PSA 2.63 to <0.01 ng/mL); Immunotherapy stopped due to expensive cost and lack of proper blood supply	Post Sipuleucel-T administration, a complete response was observed, posited to be due to MSI-H status; PSA was normalized (to 0.418 ng/mL), superior mediastinal lymph nodes were stable, and the left supraclavicular lymph node reduced with no other evidence of metastatic dx

Note. PSA = prostate-specific antigen; CAB = Combined Androgen Blockade; ADT = androgen deprivation therapy; IMRT = Intensity Modulated Radiation Therapy; LDN = Low Dose Naltrexone; CTL = Cytotoxic T lymphocyte; TIL = tumor-infiltrating lymphocyte; MRI = Magnetic Resonance Imaging; PET, positron emission tomography; NLR = Neutrophil-to-Lymphocyte Ratio; PLR, Platelet-to-Lymphocyte Ratio; MSI = Microsatellite Instability; VUS = Variance of Unknown Significance.

Mutation in AR T878A with 1.3% allele frequency. ^b VUS, c.2607+5G>A (intronic) in RET gene; somatic BRCA2 T3310fs*17 mutation (2.2% allele frequency). ^c CDK12 mutation was reported. ^d Immunohistochemical analysis showed loss of expression of MSH2 and MSH6, with retention of MLH1 and PMS2 expression. ^e Normal protein expression was seen; FoxP3 staining was specific with nuclear staining in lymphocytes, not tumor cells.

Patient Populations

Dalgleish and Liu (2022) reported the outcomes of six patients with PCa, some of which had metastases. The mean age of all participants was 61.67 ± 4.18 years.

Idossa et al. (2022) reported retrospectively reviewed outcomes of two patients with HIV, one of which had metastatic disease with no data on the second patient. The age of the participants at the time of diagnosis was 52 and 62, respectively. Programmed cell death ligand-1 testing by immunohistochemistry was not conducted for both patients (Idossa et al., 2022). Ravindranathan et al. (2021) presented two reports of patients with metastatic castration-resistant prostate cancer (mCRPC) and high microsatellite instability (MSI-H) status as detected via ctDNA aged 51 and 81 years, respectively. Han et al. (2020) reported a case of one patient with metastatic PCa aged 75 with a history of testicular seminoma when he was 30 years old. Lainez-Nuez et al. (2020) reported one patient aged 47 years who presented with Stage IV PCa. Sena et al. (2021) presented a 60-year-old male patient diagnosed with brain metastases due to PCa who had castration-resistant, mismatch repair-deficient disease with MLH1 loss.

Zhu et al. (2022) reported a case of a 55-year-old male with CDK12-mutated PCa diagnosed with the help of circulating tumor DNA. Basnet et al. (2017) present a unique case of a male patient aged 65 years with mCRPC, and primarily local failure in the pelvis. Van Bos et al. (2020) present a case of an 80-year-old patient with lymph node and bone metastatic small cell carcinoma of the prostate following low-dose-rate brachytherapy for low-risk prostate carcinoma. Cabel et al. (2017) report two male patients aged 49 and 51 years with mCRPC; both of them were enrolled in two trials (CA184-043 and CA184-095) and had undergone multiple previous interventions. Monge et al. (2018) report a case of a 79-year-old male patient with mCRPC with metastasis to the lymph nodes and bone and a history of atrial fibrillation enrolled in a clinical trial for 8 weeks.

Sharan et al.’s (2020) report comprised a 58-year-old male diagnosed with advanced PCa. The patient had been priorly diagnosed with renal cell carcinoma in 1996 (Sharan et al., 2020). Kumar et al. (2019) report a 63-year-old male who was diagnosed with prostate adenocarcinoma, which was at first organ confined and shifted to hormone-refractory metastatic disease 4 years post-initial diagnosis.

Karbach et al. (2023) report a male patient in his 70s to report a patient with PCa case with metastatic hormone-refractory New York esophageal squamous cell carcinoma 1 (NY-ESO-1). Shi et al. (2018) present a case of an 82-year-old patient with prostatic adenocarcinoma and multiple bone metastases.

Zhang et al. (2019) described a case of a 71-year-old male patient with mCRPC with metastases to the lungs, mediastinal, and supraclavicular nodes.

Immunotherapies Administered

Dalgleish and Liu (2022) administered IMM-101, which is a naturally occurring heat-killed whole-cell mycobacterium; it is used in combination with conventional treatments for prostate cancer. The patients in the series were also administered zoledronic acid, aspirin, bromelain, and low-dose naltrexone (Dalgleish & Liu, 2022).

Idossa et al. (2022) retrospectively reviewed records of 2 patients with HIV who were treated with Pembrolizumab. The therapy is FDA-approved for MSI-H mismatch repair-deficient PCa in addition to those with high tumor mutational burden (TMB). Overall, the two patients in the case report were administered therapy for 31 and 14 months with a total number of cycles of 36 and 19, respectively (Idossa et al., 2022). Ravindranathan et al. (2021) administered Pembrolizumab to two patients. The first underwent a total of 12 cycles of pembrolizumab, with no adverse events reported; the second underwent five cycles of pembrolizumab, with a good response. Both therapies were administered intravenously every 3 weeks at a dosage of 200 mg (Ravindranathan et al., 2021). Han et al. (2020) administered Pembrolizumab on a compassionate basis to one patient combined with radiotherapy (external beam). The patient was administered a total of six cycles of Pembrolizumab and continued on monotherapy on the last follow-up (Han et al., 2020). Lainez-Nuez and colleagues (2020) administered primarily Abiraterone Acetate, which was given alongside Pembrolizumab. The former medication was given 1,000 mg a day accompanied by oral Prednisone (10 mg a day) and intravenous Pembrolizumab given 200 mg, every 3 weeks (Lainez-Nuez et al., 2020). Sena and colleagues (2021) administered Pembrolizumab as the central therapy for brain metastases due to PCa. The patient was primarily treated with external beam radiotherapy (RT) and ADT. This was followed by stereotactic RT and Pembrolizumab at a dose of 200 mg every 3 weeks. The immunotherapy was continued for 6 months before the patient was shifted to Docetaxel chemotherapy (Sena et al., 2021).

Zhu et al. (2022) primarily administered Cis-Platinum chemotherapy to the CDK12 mutated PCa patient. Essentially, a literature-supported PD-1 inhibitor was administered in the last year of survival (Zhu et al., 2022). Basnet and colleagues (2017) used Nivolumab, a PD-1 blocker, as a fifth-line agent once the patient became refractory to chemotherapies and Enzalutamide. The patient underwent 19 cycles of Nivolumab, and the treatment was administered on a key basis that immunohistochemical analysis showed loss of expression of MSH2 and MSH6 with retention of MLH1 and PMS2 expression (Basnet et al., 2017). Van Bos and colleagues (2020) used Atezolizumab as an add-on therapy along with chemotherapy to manage pure small-cell carcinoma of the prostate. The patient underwent a total of six cycles of Atezolizumab, where Carboplatin and Etoposide were administered as well (Van Bos et al., 2020). Cabel and colleagues (2017) presented the single-therapy usage of Ipilimumab among two patients with a metastatic hormone-refractory disease. The patients were intervened with Ipilimumab 3-weekly and then moved onto administration every 3 months for a total of 3 years (Cabel et al., 2017). Monge et al. (2018) reported that a full timeline of treatment was not provided; however, the patient was enrolled in a Nivolumab (1 mg/kg) and PROSTVAC (every 2 weeks) combined clinical trial for 8 weeks. The therapeutic cancer vaccine and immune checkpoint inhibitor (ICI) together were utilized to induce anti-tumor activities through immunogenic intensification (Monge et al., 2018).

Sharan et al. (2020) administered a personalized dendritic cell vaccine (APCEDEN) to one patient with six doses biweekly over 3 months. The intervention was given both intradermally and intravenously (Sharan et al., 2020). Post 6 months, the patient was additionally administered six booster shots over 6 months. Kumar et al. (2019) presented a treatment history of 7 years, where personalized dendritic cell immunotherapy (APCEDEN) was commenced in the fourth-year post-diagnosis. APCEDEN was given in total over six doses, where the patient also received mitoxantrone to improve cell-mediated immunity (Kumar et al., 2019).

Karbach et al. (2023) administered both Pembrolizumab and Tumor Infiltrating Lymphocytes (TIL). Pembrolizumab (4 doses) was given before every infusion of TIL (3 sessions) over 3 years (Karbach et al., 2023). Shi and colleagues (2018) used alloreactive Cytotoxic T lymphocyte (CTL) immunotherapy, after post-initial poor response to RT and chemotherapy. A total of 28 cycles were administered of alloreactive CTL immunotherapy (Shi et al., 2018).

Zhang et al. (2019) administered Sipuleucel-T, which is an autologous cellular immunotherapy as monotherapy to contain disease progression. Standard treatment options were used including radical prostatectomy and salvage RT (Zhang et al., 2019).

Post Hoc Analysis Findings

Overall, the mean age of all 24 participants was 63.96 years (SD = 10.28). The mean Gleason score of all the included patients was 6.31 (SD = 3.65). Immunotherapies were administered in the following frequencies: Pembrolizumab (n = 8, 30.8%), IMM-101 (n = 6, 23.1%), Nivolumab (n = 2, 7.7%), APCEDEN (n = 2, 7.7%), Ipilimumab (n = 2, 7.7%), TIL (n = 2, 7.7%), Atezolizumab (n = 1, 3.8%), PD-1 inhibitor-unknown (n = 1, 3.8%), Sipuleucel-T (n = 1, 3.8%), and PROSTVAC (n = 1, 3.8%). The mean OS (post-immunotherapy) of the participants (N = 24) was 27.8 months, with a large standard deviation (SD = 22.76). In total, 21 (80.8%) patients were alive on the last follow-up. A box plot depicting the median OS (either due to death or the period until the patient was last followed) is depicted in Figure 2, with indicators of the administered immunotherapies.

Figure 2.

Median Overall Survival Post-Immunotherapy (Either at the Last Follow-Up or Due to Death), is Depicted in Months

Discussion

We reported various compassionate-use cases of 10 different immunotherapies being used among 24 patients with palliative RT, chemotherapy, or monotherapy. Our study pooled 30.8% of patients who were administered Pembrolizumab at different time points of treatment, which was the most frequently administered immunotherapy; all of the included patients were not tested in-hospital for biomarker expression of MSI-H or DNA mismatch repair (dMMR) before administration. The second most commonly administered immunotherapy was IMM-101 among 23.1% of the patients and exhibited the highest survival postadministration. The mean OS post-immunotherapy was 27.8 months (SD = 22.76); the majority of the patients had metastatic or regionally advanced PCa. Our study adds to the set of ongoing literature in synthesizing key experimental immunomodulating therapies including vaccines, TIL, oncolytic virus-mediated modalities, and others in combination with chemotherapy and/or radiation.

An estimated 3% to 5% of mCRPC patients that have MSI-HM and dMMR phenotypes express high-TMB and higher levels of TIL (Marcus et al., 2019). It is pertinent to correlate these phenotypes as the subgroup of patients may display exceptional responses to anti-PD-1 therapies including Pembrolizumab (Abida et al., 2019; Aguiar-Ibáñez et al., 2022). Zhang and Tong (2022) report that the standard of care for mCRPC that expresses high TMP and/or MSI-H is Pembrolizumab after all feasible and available treatment options. The updated treatment modality for PCa is based on pathological molecular phenotypes, not the different types of tumors. In this scenario, the U.S. FDA has approved six medications since 2017 for histology-agnostic indications. The six medications include (a) Pembrolizumab for dMMR/MSI-H and TMB-H phenotypes, (b) entrectinib, (c) Larotrectinib, (d) dostarlimab, and (e) trametinib combined with (f) dabrafenib (Zhang & Tong, 2022). Insofar as only the efficacy of Pembrolizumab in dMMR/MSI-H mCRPC has been confirmed by larger powered studies.

While the progression of PCa was varied across our cases, very few former trials have investigated the role of IMM-101 (heat-killed Mycobacterium obuense); the largest was a Phase II study that tested IMM-101 combined with gemcitabine in 110 patients with metastatic or locally advanced PCa (Stavrinides et al., 2020). The OS in the intention-to-treat population was 6.7 months for IMM-101 and gemcitabine compared with 5.6 months for gemcitabine alone (hazard ratio = .68, p = .074; Stavrinides et al., 2020). Differences in OS between the two arms in the metastatic disease subgroup were 7 versus 4.4 months in IMM-101 versus standard of care groups (p = .01) (Stavrinides et al., 2020). We find that while IMM-101 has not yet penetrated PCa care at the center stage, its use along with anti-inflammatory agents including low-dose naltrexone or bromelain may be considered a safe and active combination and ought to be considered (Dalgleish & Liu, 2022).

When considering Nivolumab, a Programmed cell death protein 1 (PD-1) blocker, and Atezolizumab, a Programmed death-ligand 1 (PD-L1) blocker, as a therapy for PCa, it is key to understand the role the PD-1/PD-L1 axis plays in outcomes of disease. In an immunohistochemical retrospective analysis of 96 cases, the PSA level, Gleason score, lymph node metastasis, and risk factor assessment were conducted by He et al. (2021). The authors found that PD-L1, not PD-l, was highly prevalent in PCa as compared with benign cases. PD-L1 expression in the tumor cells was also associated with the Gleason score but was not related to other variables. It is posited that PD-L1 is closely linked to the Gleason score, and it may be a co-variate associated with the progression of the disease. The first ever ICI to ever be studied in PCa was CTLA-4, which led to the development of human monoclonal antibodies blocking the pathway, called Ipilimumab. While the agent was developed for metastatic melanoma, it was tested in two Phase III clinical trials pre- and post-chemotherapy in mCRPC (Kwon et al., 2014; Slovin et al., 2013). While the trials did not meet their primary endpoint of improving OS, the candidate is still undergoing testing in differential settings. Large and concerted effects are underway to develop biomarkers and treatments for select patients with PCa who may benefit from mono or multitiered strategies as needed.

In our study, only one patient in this study was treated with Sipuleucel-T; it is pertinent to ascertain that it is the first dendritic cell cancer vaccine to have been approved by the FDA for mCRPC in 2010. Autologous dendritic cells derived from patients are typically supported by PCa antigens, prostatic acid phosphatase, and the support of GM-CSF (granulocyte-macrophage colony-stimulating factor; Jeong & Kwak, 2022). Insofar, as only partial responses have been noted in larger clinical trials. While the literature cites Sipuleucel-T as the first encouraging step for ICIs (Jeong & Kwak, 2022), the insufficient yield in terms of OS has enabled the testing of other therapies including TIL. Very few studies have reported the presence of TIL in the prostate gland. However, TIL has rarely been isolated under suitable conditions for adoptive cell therapy. Yunger et al. (2019) demonstrated data about prostate-specific TIL that was expanded and reactivated, was tumor-specific, and functional. The authors developed TIL adoptive cell therapy (ACT) and proposed its use as a potential strategy for the development of a personalized-based vaccine or ACT with T cells targeting mutation-derived neo-antigens, with projected benefits against PCa-associated antigens including PSA (Yunger et al., 2019).

There are certain limitations of this study. The included data are obtained from case reports/case series which is not representative of the entire population due to the small sample size of 24 patients. this means that the data, while important, must be interpreted in light of other available literature on PCa. Certain studies did not report PSA levels at the time of immunotherapy administration. Similarly, the Gleason score was not available for certain patients. Also, the previous treatments received by patients could not be made homogeneous as the studies were reported across different settings and countries. While bivariate and receiver–operating characteristic curve (ROC) analyses were initially planned in SPSS, it was not pursued due to the limited sample size of the patients. There are certain strengths of this study. This study summarized all individual cases of patients with PCa. Given the nature of this research article, a broad range of studies including different treatment timelines were included which formed a robust data pool. Finally, this study provides critical insight into the ongoing research efforts for immunotherapies being tested for PCa that will help advance the knowledge base for PCa.

Conclusion

In this systematic review and post hoc analysis, we identified a total of 16 studies that reported 24 patients with prostate cancer receiving various immunotherapies. We summarized the PSA trends, Gleason score at the time of diagnosis, secondary tumors, and overall treatment timelines before and during immunotherapy treatment. The mean age of the patients was 63.96 years with a mean Gleason score of 6.31. Ten types of immunotherapies were identified with Pembrolizumab (among 8 patients) followed by IMM-101 (among 6 patients) being the most commonly administered. The mean OS for all patients was 27.8 months with the relatively highest mean OS reported with IMM-101 (56 months) followed by TIL (30 months).

Supplemental Material

sj-docx-1-jmh-10.1177_15579883231165140 – Supplemental material for Has the Landscape of Immunotherapy for Prostate Cancer Changed? A Systematic Review and Post Hoc Analysis

Supplemental material, sj-docx-1-jmh-10.1177_15579883231165140 for Has the Landscape of Immunotherapy for Prostate Cancer Changed? A Systematic Review and Post Hoc Analysis by Muhammad Usman Ashraf, Ume Farwa, Maryam Siddiqa, Azza Sarfraz, Nishwa Azeem and Zouina Sarfraz in American Journal of Men’s Health

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Zouina Sarfraz

Supplemental Material

Supplemental material for this article is available online.

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