Cancer vaccines

Cancer vaccines
Ihab Muhammad Mahmoud
Medical Research Institute –Alexandria
Tumor Immunology
11/04/2018
18/04/2018

Cancer vaccines
Unlike prophylactic vaccines that are generally
administered to healthy individuals, therapeutic
cancer vaccines are administered to cancer
patients.

Cancer vaccines
• Cancer vaccines are designed to eradicates
cancer cells through strengthening patient’s
own immune responses.
• Cancer vaccines inhibit further growth of
advanced cancers and/or relapsed tumors that
are refractory to conventional therapies
(surgery, radiation and chemotherapy).

Cancer vaccines
• Coley’s toxin (mixed
bacterial vaccine):
injected intratumoral to
stimulate the immune
system for improving a
cancer patient’s
condition.
• Coley’s principle was
correct and the vaccine
was effective.

Cancer vaccines
• BCG is one similar example as the Coley's
Toxin, is still being used intravesically to treat
superficial bladder cancer.
• FDA has approved two prophylactic vaccines
for:
– Hepatitis B virus that can cause liver cancer (HCC).
– Human papillomavirus accounting for 70% of
cervical cancers.
• Cancer vaccines have achieved clinical proof-
of-concept of therapeutic cancer vaccines.

Cancer vaccines
• Based on their content/format, cancer
vaccines may be classified into:
1. Cell vaccines (tumor).
2. Cell vaccines (immune cells).
3. Protein/peptide vaccines.
4. Genetic (DNA, RNA and viral).

(1) Tumor cell vaccines
1. Autologous tumor cell vaccines.
2. Allogenic tumor cell vaccines.

1- Autologous tumor cell vaccines
• Prepared using patient-
derived tumor cells:
1. Tumor cells are typically
irradiated.
2. Combined with an
immunostimulatory
adjuvant (eg. BCG).
3. Administered to the
individual from whom
the tumor cells were
isolated.

• Autologous tumor cell vaccines has been
tested in various cancers:
– Lung cancer.
– Colorectal cancer.
– Melanoma.
– Renal cell cancer.

• Advantage of the whole tumor cell vaccines :
– potential to present the entire spectrum of tumor
associated antigens to the patient’s immune
system.
• Disadvantage and limitation:
– Preparation requires sufficient tumor specimen,
which limits this technology to only certain tumor
types or stage.

Autologous tumor cells may be modified to
confer higher immunostimulatory
characteristics.
• Immunization with tumor cells engineered to
express IL-12:
• Promoting Th1 immunity.
• Higher INF-γ production.
• Increased activation of CTL and NK cells.
• Tumor cell transduced with costimulatory
molecule B7-1 showed antitumor effect.

• GM-CSF-transduced autologous tumor cell vaccines(GVAX):
o Recruits DCs.
o Presentation of TAs and priming CD8+ T cells.
o Stimulates maturation of DCs by up-regulation of B7-1
expression.

• GVAX combination with CTLA-4 inhibitor, alter the
balance of T eff and T reg.
• Combination blockade of PD-1 and CTLA-4 with FVAX:
– Pd-1 interaction with PD-L1/L2 or B7-1 inhibit T cell
activation and cytokine production.
– Blockade of the negative costimulatory pathways favors
the expansion of tumor–specific T cells and maintenance
of their effector functions
– Resulting in shifting the immunosuppressive tumor
microenvironment to inflammatory/ immunostimulatory
state.
• GVAX was formulated with LPS, a TLR4 agonist:
– Enhanced antitumor effect correlated with increased
tumor infiltration by activated DCs, CD8+ and CD4+ T
cells.

2- Allogenic tumor cell vaccines
• Contain two or three established human tumor
cell lines.
• Overcome the limitations of autologaous tumor
cell vaccines.
– Limitless sources of TAs
– Standardized.
– Large-scale vaccine production.
– Reliable analysis of clinical outcomes.
– Easy manipulation for expression of
immunostimulatory molecules.
– Cost- effectiveness.

2- Allogenic tumor cell vaccines
• Canvaxin® vaccine is an allogenic whole-cell
vaccine consisting of three melanoma lines
combined with BCG as an adjuvant.
• An allogenic tumor cell vaccine
(belagenpumatucel-L) consisting of four non-
small cell lung cancer cell lines engineered to
secret antisense oligonucleotide to
immunosuppressive cytokine TGF-B.

(2) DC vaccines
• DCs are the most professional APCs.
• DCs act as sentinels at peripheral tissues.
• DCs uptake, process, and present pathogen- or
host-derived antigenic peptides to naiive T
lymphocytes at lymphoid organs.
• DCs bridging innate and adaptive immunity.
•  Cancer immunotherapeutic strategies
target DCs directly or indirectly for the
induction of antigen-specific immune
responses

(2) DC vaccines
• DC maturation signals are critical for
– avoiding the induction of T cell tolerance
– or augmentation of effective antitumor immunity.
• Three interactive signals are required for
functional activation of DCs → innate and
adaptive immunity against cancer:
1. Loading of MHC-peptide to DCs for T cell priming.
2. Costimulatory molecules such as CD40, CD80 and
CD86.
3. Production of cytokines capable to polarize a Th1/Tc
immune response.

(2) DC vaccines
1- Ex vivo generated DCs as cancer vaccines
• Preparation of DC vaccines:
– Loading tumor associated antigen to patient’s
autologous DCs (treated with adjuvants).
– These antigen-loaded, ex vivo matured DCs are
administered back into patients to induce antitumor
immunity.
• Antigens utilized:
– Tumor-derived proteins or peptides.
– Whole tumor cells.
– DNA/RNA/Virus.

(2) DC vaccines
• DC vaccines have been tested in clinical trials for
the treatment of:
– Prostate cancer.
– Melanoma.
– Renal cell carcinoma.
• Limitation: The autologous vaccine regimen
consists of :-
1. leukaphareses to isolate PBMCs from the patients
2. cell culture processing
– These limits the number of vaccinations.

(2) DC vaccines
• Sipuleucel-T (Provenge®)FDA approved for
treatment of metastatic castrate-resistant
prostate cancer.
• This vaccine consists of APCs contain prostatic
acid phosphatase (PAP, a prostate antigen)
fused with GM-CSF.
• Sipuleucel-T as the first therapeutic cancer
vaccine.

(2) DC vaccines
• Autologous DCs are
isolated from a patient’s
blood and cultured with
a fusion protein
consisting of the
prostate cancer specific
antigen PAP and the
APC-activating cytokine
GM-CSF (PAP/GM-CSF).

(2) DC vaccines
• DCs take up and process
these antigens, after
which they are
reinfused into the
patient in order to
stimulate a T-cell
response against PAP
expressed on tumor
cells in the prostate.

(2) DC vaccines
2- Modification of DC to improve vaccine
potency
• Despite the clinical success of APC-based
prostate cancer vaccines, the modest
antitumor efficacy of Sipuleucel-T emphasize
the need for improvement and optimization of
this approach.

(2) DC vaccines
potency
• T cell activation is controlled by co-stimulatory
molecules expressed on DCs.
• Modification in the expression levels of
activating or inhibitory molecules could
enhance the DC vaccine potency.
• CD40 stimulation on DCs (by activated CD4+
T cells) is required for DC licensing and cross-
priming of CD8+ T cell responses.

(2) DC vaccines
potency
1. CD40L overexpression in mouse via
– virus transduction..
– mRNA electroporation led to :
– elevated expression of B-7 molecules
– enhanced IL-12p70
– Th1 antitumor immunity.

(2) DC vaccines
potency
2. Modulation of:
– Stimulatory molecules, such as ; CD70, 4-1BBl and
OX40L
– Or pro-inflammatory factors, such as ; IL-12p70,
IL-2, IL-18, CCR7 and CXCL10
– Enhance DC function→ maturation, activation,
migration and capacity to stimulate antigen-
specific Th1 and CTL responses.

(2) DC vaccines
potency
3. A20 (ubiquitin-editing enzyme, negatively
regulates both TLRs and TNF receptors
signaling-induced maturation of DCs) silencing
in human DCs :
→Facilitates the development of INF-γ producing
Th1 cells and antigen-specific CD8+ T cells.

(2) DC vaccines
potency
4. SRA/CD204 (attenuates TLR4-engaged NF-
kB-TRAF6 signaling pathways in DCs and
downregulates the immunogenicity of DCs
and CTL-mediated antitumor immunity)
absence or silencing :
→enhances the immunostimulating, antigen-
presenting functions of DCs.

(3) Protein/peptide-based cancer
vaccines
• Limitations of autologous cancer vaccines
(whole tumor cell & DC’s):
– Availability of patient’s samples.
– Complex procedure of preparing individualized
vaccines.

(3) Protein/peptide-based cancer
vaccines
1. Tumor-associated antigens as therapeutic
targets.
2. Immunostimulatory adjuvants for
protein/peptide-based vaccines.

(3) Protein/peptide-based cancer vaccines
1-Tumor-associated antigens as therapeutic
targets.
• Recombinant vaccines, which are based on
peptides from defined
– tumor-associated antigens(TAA),
– tumor specific antigens (TSA),
– or other tumor antigens
• administered together with adjuvant or an
immune modulator.

targets.
• MAGE-1 gene was the first reported to encode
a human tumor antigen recognized by T-cells.

targets.
• Antigens may be classified into several majour
categories:
1. Cancer testis antigens (MAGE, BAGE,…)
2. Tissue differentiation antigens : of normal
tissue origin shared by both normal and
tumors:
– Melanoma: (gp100, Melan-A, tyrosinase,..).
– Prostate cancer: (PSA,PAP).
– Breast carcinomas: (mammoglobin-A).

targets
3. Tumor differentiation-associated antigens:
– CEA.
– HER2/Neu
– Tumor suppressor gene : (p53).
– Anti-appoptotic protiens.
4. Tumor specific antigens are often mutated
oncogens (Ras,..)
– Adv. more effective.

targets
• Advantage:
– Protein/peptide-based cancer vaccines
are most cost effective than autologous or
individualized vaccines.
• Disadvantage:
– Target only one epitope or few epitopes of TAA for
induction of both antigen-specific CTLs and
antigen specific CD4+ helper t-cells.

2-Immunostimulatory adjuvants for
• TAAs are poorly immunogenic in nature.
• Immunostimulatory adjuvant is essential for
generation of an effective immune response
eg. Aluminum salts (alum).
• Radical altered theories as how adjuvants
promote adaptive immunity.
• Adaptive immune responses are preceded by,
and dependent on, innate immunity receptors
(PAMPs eg. TLRs).

• TLR-mediated activation of APCs (eg. DCs) is a
crucial step.
• Experimental vaccines incorporate PAMPs
(molecularly and functionally defined
molecules as adjuvant) as a part of
therapeutic immunizations against cancer.

• TLR agonists have strong potential in
promoting the immunogenicity of weakly
immnunogenic TAAs.
– Several protein/peptide-based cancer vaccines
combined with TLR agonists being tested in clinical
trials.
– Eg.BCG (TLR agonist) used in the treatment of
bladder carcinoma, show to activate TLR2 and
TLR4.

• As PAMPs sense exogenous signals, DAMPS
(damaged-associated molecular patterns) are
intrinsic (endogenous) alarmins eg. HSPs.
• Stress/Heat shock proteins (HSPs) are capable
of integrating both innate and adaptive
immune responses, utilized as
immunostimulatory agents for cancer
vaccines.

• HSPs isolated from cancer cells were able to
induce tumor immunity.
• First autologous HSP vaccine , Oncophage®
approved in Russia as adjuvant in the
treatment RCC.
• Over coming technical difficulties (tumor
specimen requirement, time-consuming
preparation, ……) formulation of recombinant
HSP vaccines.

(4) Genetic vaccines
• Utilizing viral or plasmid DNA vectors carrying
the expression cassettes to deliver antigen or
antigen fragments in vivo.
• They transfect somatic cells (myocytes,
keratinocyte) or DCs that infiltrate muscle or
skin as a part of the inflammatory response to
vaccination.
• Cross-priming or direct antigen presentation.

• Advantage:
– Easy delivery of multiple antigens in one
immunization.
– Activation of various arms of the immunity.
• Types of genetic vaccines:
– DNA vaccines.
– RNA vaccines.
– Viral-based vaccines.

1- DNA Vaccines
• DNA vaccines are bacterial plasmids (vector).
• Function as shuttle system to deliver and express
tumor antigens.
• For generation of targeted humoral and cellular
immunity.
• The backbone of bacterial DNA acts as PAMPs to
stimulate activation of immune cells through
– TLRs or
– other innate pattern recognition molecules (PRR).

1- DNA Vaccines
• Incorporate multiple genes → modulate
intracellular routing and modification of
antigens.
– eg. Addition of a leader sequence to target
antigens to the endoplasmic reticulum induce:
• Humoral response.
• Generation of CD8+ T cell response.

1- DNA Vaccines
• Combined with costimmunaltory agents to
optimize antibody response (eg. TLRs agonist):
– eg. : DNA cancer vaccine targeting HER2/Neu or
CEA used with TLR9 agonist.
•  Antibody titers.
•  ADCC activity.
– Improvement control of:
• HER2- positive mammary carcinoma.
• CEA- positive colon carcinoma.

1- DNA Vaccines
• Fusion of the TAAs (poor immunogenicity) and
non-self antigens or molecules (virus coat, modified
fragment C of tetanus toxin,..)
– → T helper signal to CTLs
–  enhanced cross-presentation of TAAs and
antitumor immunity.

1- DNA Vaccines
• DNA vaccine for vascular endothelial growth
factor receptor 2 :
– CTL-mediated killing of endothelial cells
– Therapeutic efficacy against:
• Melanoma
• Colon carcinoma
• Lung carcinoma

1- DNA Vaccines
• DNA vaccine (oral) encoding human endothelial
marker 8:
– → Suppress angiogenesis.
• DNA vaccine encoding HPV E7 fused with
calreticulin:
– → Strong CD8+ T cell response.
–  Immune mediated attack of both cancer cells and
endothelial cells.
• DNA vaccine targeting angiostatin receptor :
– → Immune mediated blockade of angiogenesis.
–  Tumor inhibition.

2- RNA Vaccines
• mRNA from autologous tumor tissues can be
used to induce CTL response.
• Total RNA vaccine generate immune response
against various tumor antigens.
• Due to rapid degradation and clearance :
– Less side effects and autoimmune diseases than DNA
vaccines.
– Carried out with stabilizing agents or adjuvants (eg.
liposomes).
– Integrating replicase polyprotein (self replication).
– Using beta-globin UTR → stabilization → enhanced
antigen-specific immune response.

3- Viral Vaccines
• What is the rationale for using viruses as
immunization vehicles ?
– Based on the phenomenon that viral infection often
result in the presentation of MHC class I/II restricted,
virus-specific peptides on infected cells.
• The viral vector:
– Engineered to encode TAAs or TAAs combined with
immunomodulating molecules.
– Low disease-causing potential.
– Low intrinsic immunogenicity.

3- Viral Vaccines
• Vaccinia virus (poxviridae family) most
extensively evaluated viral-based vectors in
cancer vaccine trials due to;
– Ability to accommodate large or several transgene
inserts.
– Replication and transcription are restricted to the
cytoplasm (minimizes risk to the host of insertional
mutagenesis).
– Induction of local inflammatory response by the host
TLRs.
– Enhance immune response reactive with inserted
TAAs.

3- Viral Vaccines
• PROSTVAC® consists of:
1. Replication-comptent vaccinia priming vector.
2. Replication-incomptent fowlpox-boosting vector.
3. Each vector contains transgenes for PSA and
three costimulatory molecules (CD80, CD54 and
DC58).

3- Viral Vaccines
• TROVAX® is a modified vaccinia strain Ankara
(MVA) vector-based cancer vaccine targeting
renal cell carcinoma antigen 5T4.
• Another MVA vector-based vaccine consists of
expression cassettes encoding MUC1 antigen
and IL-2.

3- Viral Vaccines
• Recombinant adenovirus system:
1. Easy to engineer and propagate to high yields.
2. Transducing both dividing and non-dividing cells
for high expression of transgenes.
3. Adenovirus vectors expressing various TAAs(PSA,
HER2/Neu) are currently being tested for their
clinical efficacy.
4. Newer less immunogenic variants of
adenoviruses and local delivery of adenovirus-
based vaccines

3- Viral Vaccines
• Herpes simplex virus type 1 (HSV-1):
– Enveloped dsDNA virus
– Ability to infect a wide variety of cell types.
– Ability to incorporate singl or multiple transgenes.
• ONCOVEX GM-CSF®
– An oncolytic HSV-1 encoding GM-CSF.
– Direct injected into accessible melanoma lesions
– Direct oncolytic activity in injected tumors.
– Secondary immune-mediated antitumor effect.

3- Viral Vaccines
• Like viral vectors, bacteria and yeast have shown
utility as vaccine vehicles in preclinical studies.
• Modified for immunizing cancer patients.
• Attenuated recombinant Listeria monocytogenes
induce innate and adaptive antitumor response.
• Saccharomyces cerevisiae inherently
nonpathogenic and can be easily engineered and
propagated for preparation of a TAA-targeted
vaccine.

Reference
• Chunqing Guo, Masoud H. Manjili, John R.
Subjeck, Devanand Sarkar, Paul B.Fisher, and
Xiang-Yang Wang. Therapeutic Cancer
Vaccines: Past, Present and Future. Adv
Cancer Res. 2013 ; 119: 421–475.

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