Immunotherapy in Urologic Oncology.ppt

IMMUNOLOGY AND IMMUNOTHERAPY IN
UROLOGIC ONCOLOGY
PRESENTER: Dr. Keagan Kirugo, PGY 4 Urology
SUPERVISORS:
Dr. Peter Oyiro; Consultant Haemato-oncologist and Lecturer, UoN,
Department of Clinical Medicine and Therapeutics.
Dr. James Ikol; Consultant Urologist and Head of Urology Unit, KNH
DATE: 28/03/2022
University of Nairobi ISO 9001:2015 1 Certified http://www.uonbi.ac.ke

1. Relevant immunology
2. Mechanism of evasion by cancer cells
3. Mechanism of immunotherapy
4. Immunotherapeutic strategies
5. Immunotherapy in Renal Cancer
6. Immunotherapy in UTUC
OBJECTIVES

7. Immunotherapy in Bladder Cancer
8. Immunotherapy in Penile Cancer
9. Immunotherapy in Testicular Cancer

Introduction
The immune system plays a major role in cancer prevention and
delaying cancer progression.
It comprises adaptive and innate immune system.
The adaptive immune system comprises lymphocytes; T cells
which carries out cell mediated immunity and B cells which
produces antibodies.
RELEVANT IMMUNOLOGY

During lymphopoiesis, rearrangement results in lymphocytes with
a diverse repertoire of unique receptors which recognize a wide
range of antigen sequences both self and non self. The
lymphocytes specific to self are usually deleted or inactivated.
During a primary response to a non self antigen, lymphocytes
specific to that antigen undergo clonal expansion, effector T and B
cells are activated, and the long-lived memory B cells persist.

Adapted from Dranoff G. Cytokines in cancer pathogenesis and cancer
therapy. Nat Rev Cancer. 2004;4(1):11-22. Crossref | PubMed

T cell Antigen Recognition
T cell antigens are presented to the T cells by specialized antigen
presenting cells (APCs), the most efficient of which is the dendritic
cell.
Recognition is sequence specific bound in the MHC molecule.
T cells must have the ability to respond to non self antigens but
must be tolerant to self antigens to avoid autoimmunity.

Adapted from https://courses.lumenlearning.com/wm-biology2/chapter/t-and-b-
lymphocytes/

MHC is present in virtually all nucleated cells, permitting CD8+ T
cells to scan intracellular antigens and identify or kill infected cells
and those expressing altered cell peptides.
The T cell receptor (TCR) does not recognize antigens alone but sees
both the MHC and peptide complexed with it, therefore the whole
complex defines the specificity of the TCR.
Once activated, T cells can mediate cytotoxicity.

Cancer cells can evade detection and eradication by the immune
system by:
1. Reducing antigen expression
2. Secreting immune-suppressing cytokines
3. Upregulating inbuilt regulatory signals
EVASION OF THE IMMUNE
SYSTEM BY CANCER CELLS

1. Eliminating viruses that drive neoplasia
2. Resolving acute inflammation to pathogens, preventing a
chronic inflammatory environment that can influence
neoplastic transformation.
3. Identifying and eliminating transformed cells
MECHANISM OF
IMMUNOTHERAPY

IMMUNOTHERAPEUTIC
STRATEGIES
1. Therapeutic Vaccination
Dendritic cell-based activation
Personalized neoantigen specific cancer vaccines
Autologous tumour cell vaccines

Dendritic cell-based vaccination
Adapted from Farkona S, Diamandis EP, Blasutig IM. Cancer immunotherapy:
the beginning of the end of cancer? BMC
Med. 2016;14(1):73. Crossref | PubMed

Tumour antigens are procured from either resection or peripheral
blood mononuclear cells.
The target is selected using DNA and RNA sequencing to identify
tumour specific mutations.
HLA-typing is carried out with prediction of personalized HLA-
binding peptides.
The personal vaccine is manufactured and administered with a
priming period of frequent repeated vaccines and subsequent
booster doses.
Personalized neoantigen-
specific cancer vaccines

The tumour itself may also represent a source of endogenous
antigens, given that anti-cancer T cells can be produced
spontaneously.
Accessing this source of antigens affords convenience.
Autologous tumour cell vaccines

Limited response due to:
1. Continued uncertainties regarding which antigens should be
used, how they should be delivered, which adjuncts are needed
and how a T cell response should manifest.
2. Presence of agents that disrupt pathogens in the tumour
microenvironment may dampen or disable anti-tumour immune
responses before clinically relevant tumour killing can occur.
Disadvantages of therapeutic
vaccines

2. Targeting immunological checkpoints
Immune checkpoints are regulators of the immune system and
enable self-tolerance. This prevents unwanted attacks on cells.
Inhibitory checkpoint molecules are targets for cancer
immunotherapy.
Examples are Programmed death-ligand 1 (PD-L1) and programmed
death receptor 1 (PD-1)

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a regulatory molecule
that suppresses T cell effector function following initial activation by
costimulatory signals.
Programmed death ligand-1 (PD-L1, also known as B7-H1), which
binds to the programmed death-1 receptor (PD-1) on the T cell
surface to inhibit T cell function
Treatments based on monoclonal antibodies that target PD-L1 or
PD-1 are now approved in many tumour types

Adapted from
https://www.researchgate.net/publication/311968982_Potential_role_of_immunotherapy_in_
advanced_non-small-cell_lung_cancer/figures?lo=1

Adapted from Dong H. The Basic Concepts in Cancer Immunology and
Immunotherapy. In: Dong H, Markovic SN, eds. The Basics of Cancer
Immunotherapy. Cham: Springer International Publishing; 2018:1-19.

1. VEGF TARGETED THERAPY
Vascular endothelial growth factor (VEGF) is a pro-angiogenic
peptide growth factor that activates a major tyrosine kinase-
signalling pathway.
VEGF is overexpressed in most sporadic renal cell carcinoma (RCC),
due to hypoxia-inducible factor-1 (HIF-1) overexpression caused by
inactivation of the Von Hippel-Lindau (VHL) tumour suppressor
gene.
IMMUNOTHERAPY IN RENAL
CANCERS

VEGF-targeted therapies increase progression-free survival and/or
overall survival, either as a first- or second-line treatments for
patients with clear cell metastatic RCC.
EXAMPLE
Bevacizumab

2. TYROSINE KINASE INHIBITORS
Protein kinases, a class of enzymes that govern various biological
phenomena at a cellular level, are responsible for signal
transduction in cells that regulate cellular proliferation,
differentiation, and growth.
Protein kinase enzyme mutation results in abnormal cell division
leading to a pathological condition like cancer.

MECHANISM OF ACTION
Kinases control cell growth and division: blocking the kinases
leads to cell death.
They also prevent neovascularization of cancer cells, reducing
their supply of oxygen and nutrients which in turn slows down
or stops the growth of the cancer.

EXAMPLES
Sorafenib: Has broad spectrum activity in a spectrum of settings in
clear cell RCC patients previously treated with cytokine and targeted
therapies.
Sunitinib: More effective than interferon alpha in treatment naïve
patients.
It is available locally in its original form under brand name SUTENT.
Both sorafenib and sunitinib have limited oncological efficacy in on
clear cell RCC.

Sunitinib is available at Nairobi Hospital under a free access
program (Managed Access System). The program has been
decentralized to Mombasa, Kisumu and Nakuru.
A lot of bureaucracy involved in importing Axitinib.

Pazopanib: First line treatment in clear cell RCC and superior to
sunitinib.
Axitinib: Used in the treatment of metastatic RCC or as
neoadjuvant therapy.
It has efficacy in PFS as 2nd line treatment failure of VEGF therapy cf
sorafenib.
Therefore, administered after treatment with another TKI or after
interferon or interleukin treatment

Cabozatinib: Used in intermediate and poor risk untreated clear cell
RCC.
Better response rates and PFS but not OS cf sunitinib.
Levacitinib: Combined with everolimus, confers a modest
improvement in PFS.
Tivozanib: Has been approved but current evidence is considered
inferior cf alternate choices.

Papillary Metastatic RCC

SIDE EFFECTS
Common
Skin: Hand and foot skin reaction
Musculoskeletal: Arthralgia, myalgia
CVS: Hypertension
Endocrine: Hypothyroidism
CNS: Lethargy

Adapted from https://onlinelibrary.wiley.com/doi/10.1111/j.1346-8138.2010.01059.x

LESS COMMON
GIT: Altered liver function
CVS: VTE
ENDOCRINE: Overactive thyroid
CNS: Confusion
HAEMATOLOGY: Anaemia
EYE: Altered vision
EAR: Tinnitus

TKIs have been described as dirty because of the SEs. Most patients
locally cannot tolerate sunitinib, especially ladies. Weight-dose
discrepancy?

2. MTOR INHIBITORS
Mechanistic target of rapamycin (mTOR) is a cellular protein that
regulates cell division and growth and is overactive in cancer cells.
It is a downstream of the tyrosine kinase signaling pathway.

MOA
Blocking mTOR leads to slowing or stopping cancer growth directly.
It acts indirectly by inhibiting angiogenesis therefore slowing or
stopping tumour growth.

EXAMPLES
Temsirolimus: Treatment of metastatic renal cancer.
As monotherapy, it prolongs OS cf interferon alpha in untreated,
poor risk metastatic RCC.
Everolimus: Inferior to Cabozatinib in PFS and OS in patients
treated with one or more lines of VEGF therapy. However,
everolimus prolongs PFS after VEGF targeted therapy cf placebo or
when patient are intolerant to VEGF targeted therapies.

Everolimus and Lenvatinib has demonstrated a PFS of 14.6/12 cf
5.5/12 in the everolimus group. This combination has therefore
been approved for use in metastatic RCC post one line of TKI.

SIDE EFFECTS
Common
GIT: sore mouth, altered taste, loss of appetite diarrhea, nausea,
indigestion
SKIN: dermatitis
CNS: lethargy, headache, insomnia
HAEMAT: anaemia, neutropenia, thrombocytopenia

Adapted from
https://www.hmpgloballearningnetwork.com/site/thederm/site/cathlab/event/derm-
dx-what-red-rash-leg

CVS: Oedema
MUSCULOSKELETAL: Arthralgia
Less Common
GIT: altered liver function, reactivation of Hepatitis B infection
RENAL: altered renal function
NS: peripheral neuropathy
SKIN: swelling and redness of hands and feet

SYSTEMIC TREATMENT FOR ADVANCED OR METASTATIC RENAL
CANCER
Interferon alpha and bevacizumab
Interferon was previously used to treat advanced RC but is currently
rarely used. This is because interferon alpha monotherapy is
inferior to VEGF targeted therapy or mTOR inhibition in metastatic
RCC.

Adding bevacizumab to interferon alpha is more effective than IF
alpha monotherapy in treatment naive, low risk and intermediate
risk RCC.

Interleukin 2 Monotherapy
It is effective in selected cases with good performance status, clear
cell RCC and lung metastasis only.
It has more side effects than IF alpha. Administered in CCU.

Immune Checkpoint Blockade
PD-1 Inhibitors
Nivolumab is a monoclonal antibody that targets PD-1.
Superior OS cf everolimus in patients failing one or two lines of
VEGF targeted therapy.
Pembrolizumab

SIDE EFFECTS
Common
SKIN: skin changes
CNS: fatigue
GIT: nausea, diarrhoea
CVS: hypertension

Anti-CTLA 4 Antibody Treatment
Ipilimumab is a monoclonal antibody that targets CTLA 4.
CTLA 4 protein on the surface of T cells can sometimes stop the
anticancer action.
Blockage of CTLA 4 allows the T cells to go on and destroy the
cancer cells.

SIDE EFFECTS
GIT: diarrhoea, altered liver function
SKIN: dermatitis
ENDO:
RESP:
CVS:
CNS: neuropathy

COMBINATION THERAPIES
World over, combination therapies are the standard.
1. Immune Checkpoint Inhibitors
Nivolumab and ipilimumab in untreated patients with clear cell RCC
of an intermediate or poor risk leads to superior OS cf sunitinib.
Associated with 15% grade 3-5 toxicity and 1.5% treatment related
deaths.

2. TKIs and Immune Checkpoint Inhibitors
JAVELIN 101 Study: Avelumab and Axitinib had a PFS of 13.8/12 cf
sunitinib at 8.4/12.
Pembrolizumab and Axitinib showed a PFS of 15.1/12 and 11.1/12
in the sunitinib arm in 1st line treatment of clear cell advanced RCC
patients.

First line for the Cisplatin Ineligible
Pembrolizumab and atezolizumab are approved for patients with
advanced or metastatic urothelial ca who are ineligible to cisplatin
first line chemotherapy.
Restricted to PDL-1 positive.
UTUC

Second line for the Platinum Pretreated
Pembrolizumab, atezolizumab, nivolumab, avelumab and
durvalumab have been used in patients progressing during or after
platinum-based chemotherapy.

NON-MUSCLE INVASIVE BLADDER CANCER
BCG IMMUNOTHERAPY
Live attenuated M. bovis
Intravesical route.
It reduces risk of disease progression and recurrence when
administered post TURBT.
BLADDER CANCER

For optimal efficacy, it must be administered in a maintenance
schedule for at least one year of treatment.
3-year maintenance therapy is more effective than one year in
preventing recurrence in high-risk patients but not in intermediate
risk.

MOA
It attaches to the urothelium via fibronectin receptor mediating an
immune response by chemotaxis and cytokine production.

SIDE EFFECTS
Local
Cystitis
Haematuria
Symptomatic granulomatous prostatitis
Epididymo-orchitis

Systemic
Malaise
Fever
Arthralgia and arthritis
Allergic reactions
BCG Sepsis

INTERFERON
IF alpha and systemic immunotherapy provide alternate treatment
options.
No clear difference in recurrence or progression with BCG and IF
alpha cf BCG. Alternating BCG with IF alpha may increase time to
recurrence however the quality of the 5 trials used in the
metanalysis was poor.

MUSCLE INVASIVE BLADDER CANCER
Check point inhibitors have no role currently in MIBC treatment.

METASTATIC DISEASE
Denosumab has been approved as supportive treatment in bone
mets in all cancer types including urothelial.
It is a monoclonal antibody that binds to and neutralizes apoptosis
regulator gene.
Superior to zoledronic acid in reducing and delaying skeletal related
events.

SIPULEUCEL-T
First ever cancer vaccine to achieve FDA approval in April 2010 as tx
for mCRPC.
APCs stimulate T-cell immune response targeted against prostatic
acid phosphatase (PAP)
Harvested APCs are incubated with recombinant fusion protein
antigen, which contains both PAP and GM–CSF.
PROSTATE CANCER

No PSA decline and no difference in PFS in minimally invasive
mCRPC when compared to placebo.
No longer available in Europe.

CHIMERIC ANTIGEN RECEPTOR (CAR)-T THERAPY
Experimental stages.
Proven efficacy in haematological cancers with potential to
become viable tx option in solid cancers including prostate.

PD/PD-L1
Trial with enzalutamide.
PL-L1 being expressed in prostate ca cells post enzalutamide.

5-FU and Imiquimod have a role in non-invasive penile cancer.
VGX-3100 targets the genetic code of HPV 16 and HPV 18 has been
used in women with ca cervix associated with HPV.
PDL-1 Inhibitors e.g., Nivolumab may be efficacious as 62.2 % of the
tumour demonstrating PDL-1.
PENILE CANCER

Highly treatable with chemotherapy but immunotherapy is
developing a role in those refractory to platinum-based CTX or
relapsing after autologous stem cell treatments.
PDL1 inhibitors (Pembrolizumab and nivolumab) have been used in
this role with newer check point inhibitors poised for use in trial in
similar fashion.
TESTICULAR CANCER

COVID-19 should not prevent immunotherapy.
COVID-19

1. Buchbinder, E., & Hodi, F. S. (2015). Cytotoxic T lymphocyte
antigen-4 and immune checkpoint blockade. The Journal of
clinical investigation, 125(9), 3377–3383.
2. Dranoff G. Cytokines in cancer pathogenesis and cancer therapy.
Nat Rev Cancer. 2004;4(1):11-22. Crossref | PubMed
3. Velcheti V, Schalper K. Basic overview of current immunotherapy
approaches in cancer. Am Soc Clin Oncol Educ Book.
2016;35:298-308. Crossref | PubMed
REFERENCES

4. Farkona S, Diamandis EP, Blasutig IM. Cancer immunotherapy:
the beginning of the end of cancer? BMC Med. 2016;14(1):73.
Crossref | PubMed
5. Aishwarya Shinde, Kanan Panchal, Sumeet Katke, Rishi Paliwal,
Akash Chaurasiya; Tyrosine kinase inhibitors as next generation
oncological therapeutics: Current strategies, limitations and future
perspectives, Therapies, 2021.

6. ESMO Clinical Practice Guideline update on the use of
immunotherapy in early stage and advanced renal cell carcinoma
2021
7. Prof. Nicholas Abinya’s talk on “MANAGEMENT OF ADVANCED
KIDNEY CANCER IN THE ERA OF IMMUNOTHERAPIES AND
PRECISION ONCOLOGY ” given as part of KESHO CMEs on March
17th, 2022.

8. Partin A, Dmochowski R, Kavoussi L, Peters C. Campbell-Walsh-
Wein Urology. 12th ed. Amsterdam, Netherlands. Elsevier.
9. EAU Guidelines 2021

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