This document provides a literature review on the application of antigen-specific immunotherapy therapeutics in prostate adenocarcinoma. It first discusses prostate cancer as a worldwide health problem and how it is diagnosed using digital rectal exams, PSA tests, and biopsies. It then explains how prostate cancer is driven by androgen receptor signaling and describes current treatment options and their limitations. Finally, it introduces antigen-specific immunotherapy as a potential solution, describing the ProstVac VF vaccine clinical trials which demonstrated improved overall survival rates for metastatic castration-resistant prostate cancer patients.

1. Application of Antigen-Specific
Immunotherapy Therapeutics
in Prostate Adenocarcinoma: A
Literature Review
By Jamie Cooper

2. Background Information
 Bray et al. (2018) conducted a worldwide cancer mortality study and estimated that
there will be 18.1 million new cases and 9.6 million cancer related deaths worldwide in
2018 and therefore acknowledging cancer as a significant worldwide health problem.
 A significant contributor to the cases and related deaths is cancer of the prostate.
Cancer of the prostate can be characterised as an adenocarcinoma resulting from the
primarily development from the glandular part of the organ which shows typical
glandular patterns (Leslie et al, 2018).
 Regardless of recent developments of therapeutics in prostate cancer it’s still the
second most commonly diagnosed nonskin cancer with an estimated 1.3 million new
cases and 359,000 associated deaths worldwide in 2018 (Bray et al., 2018).

3. What is the structure and function of the
prostate?
 The prostate gland is characterised as the largest accessory gland of the male
reproductive system (Bhavsar & Verma, 2014).
 The prostate is mainly made up of glandular tissue which functions to produce fluid
that constitutes to semen which helps nourishes the sperm and maintain a high pH
(Leslie et al, 2018).
 The human prostate can be described as a walnut sized organ which
surrounds the urethra and base of the urinary bladder (Aaron et al,
2016).
 The prostate can be divided into four regions, the central zone (CZ),
peripheral zone (PZ), transition zone (TZ) and the anterior fibromuscular
stroma (AFS) (Bhavsar & Verma, 2014).

4. Diagnosing Prostate Adenocarcinoma –
How?
 Diagnosing Prostate Adenocarcinoma can occur by either a digital rectal exam (DRE),
Prostate-specific antigen (PSA) test and occasionally a transrectal prostate biopsy
(Kaplan, 2007).
Digital Rectal Exam
• DRE is commonly incorporated as part of a routine in
primary care for examination in men for prostate cancer
(Wallner et al., 2012).
• The procedure works by insertion of a lubricated gloved
finger into the rectum and feeling the prostate through
the rectal wall for lumps or abnormal areas (Babcock et al,
2019).
Prostate-specific Antigen Test
• PSA is a glycoprotein that is directly secreted via the
prostatic epithelium and is not tumour specific as it can be
expressed by either normal or malignant prostate cells
(Ingle & Ingle Ramona, 2013).
• The test works by taking a blood sample from a patient
and manipulating the sample within the laboratory to
quantify the levels of PSA in nanograms per millilitre of
blood (ng/ml) (Végvári et al., 2013).
• Normal levels of PSA in healthy males are usually <4ng/ml
and anything above the reference range have been
reported in 50% in stage A, 80% stage B and 100% stage C
and D prostate cancer (Ingle & Ingle Ramona, 2013).
Transrectal prostate biopsy
• A transrectal prostate biopsy works by removing tissue by
the insertion of a thin needle through the rectum into the
prostate which is guided by transrectal ultrasound or MRI,
a pathologist then views the tissue under a microscope to
determine if any cancerous cells are present

5. Pathophysiology of Prostate
Adenocarcinoma (Androgen Receptor
Signalling)
 The causation of prostate adenocarcinoma is down to a wide range of risk factors such
as being of the male gender, older age, positive family history, obesity, hypertension,
lack of exercise, persistently elevated testosterone levels and ethnicity (Leslie et al,
2018).
 Academic studies have elucidated that prostate cancer is characterised by the androgen
receptor (AR) signalling which is a ligand-dependent nuclear transcription factor and a
member of the steroid hormone nuclear receptor family (Davey & Grossmann, 2016).
 The human AR is encoded by a single copy of the gene situated on the X-chromosome
producing a 919 amino acid length protein containing poly-glutamine, poly-glycine and
poly proline repeats variable in lengths (Velcheti et al., 2008).
The three main functional domains of the human AR: N-terminal domain (NTD), DNA binding domain (DBD)
and the C-terminal ligand-binding domain (LBD) (Davey & Grossmann, 2016).

7. Therapeutics Of Prostate Cancer
 Patients that develop localised prostate cancer are often treated with novel therapies
such as surgery and radiotherapy (Heidenreich et al., 2014).
 Different patients which are affected by an alternative prostate cancer which has spread
to others part of the body termed metastatic; undergo androgen deprivation therapy
(ADT) which goal is to reduce androgens in the body to stop them stimulating cancer
cell growth (Gomella, 2009).
 Often with ADT a disease state termed castration-resistant prostate cancer (CRPC) can
be established, which is the apparent progression of the tumour despite ADT meaning
the therapeutic technique has become obsolete (Saad & Hotte, 2010).
 For CRPC patients the novel therapeutic treatment is docetaxel-based chemotherapy
which is the introduction of radioactive chemotherapy agents which target cancerous
cells and stops them dividing (Shewach & Kuchta, 2009).
PROBLEM!

8. Therapeutics Of Prostate Cancer
PROBLEM!
 This treatment however can be problematic as patients can show primary resistance to
chemotherapy agents and therefore the therapeutic technique also becomes obsolete
(Buttigliero et al., 2015).
 Therefore, alternative therapeutic strategies are essential to improve the survival rates
of patients with advanced and metastatic prostate cancer (Heidenreich et al., 2014).
Solution?
Immunotherapy!

9. What Is Antigen-Specific Immunotherapy
and how it works?
 In the field of immunology immunotherapy aims to elucidate treatments for
disease through induction, enhancement or suppression of an immune
response (Wraith, 2017).
 Prostate Adenocarcinoma has characteristics to which makes it suitable for
immunotherapy such as..

10. What Is Antigen-Specific Immunotherapy
and how it works?
 Different cell types which can recognise and destroy tumour cells include
macrophages, antigen-presenting cells (APCs), CD8+ CTL cells and natural
killer cells (Noguchi et al., 2017).
 By generating an antigen-specific immune response by introducing tumour
antigens to T cells by APCs these different cell types have the potentiality in
recognising and therefore destroying tumour cells (Drake, 2014).

11. Clinical Trail: Application of Antigen-Specific
Immunotherapy in Prostate Adenocarcinoma

12. ProstVac VF
 The ProstVac VF vaccine contains DNA plasmid encoding the target antigen,
PSA and three co-stimulatory molecules such as lymphocyte function-
associated antigen 3 (LFA3), intercellular adhesion molecule 1 (ICAM1) and
CD80 (Drake, 2010).
 The incorporation of CD80 within the vector facilitates the activation of T
cells, as well LFA3 and ICAM1 co-stimulating T cell activation (Drake, 2010).

13. ProstVac VF
 A phase II trial conducted by Kantoff et al. (2010) randomised a total of 122
metastatic castration-resistant prostate cancer patients to receive the vaccine
vs. placebo in a 2:1 ratio.
 Results suggested an improvement of overall survival by 8.5 months as well
as a 44% reduction in mortality rate.
 The data was further revised by Kantoff et al. (2016) and demonstrated that
in fact a survival advantage increased to an overall 9.9 months (P = 0.0019).

14. Thanks For Listening