Bacteria in cancer therapy

1. BACTERIA IN CANCER THERAPY
Presented by – GAURAV GANGWAR

2. INTRODUCTION
• Therapies like photodynamic therapy,
HAMLET(human alpha-lactalbumin made lethal
to tumor cell), gene therapy, complementary
and alternative therapy etc. are intended or
claimed to treat cancer.
• But a Live, attenuated, genetically modified,
non-pathogenic bacterial species and bacterial
spores are also capable of inhibiting the growth
of cancer.
• The most potential and promising strategy is
bacteria based gene-directed enzyme prodrug
therapy.

3. HISTORY
• Observation of German physicians W. busch &
F. fehleisen..
• American physician William coley.
‘coley’s toxins’ – Two heat killed bacterial
species, Salmonella pyogenes and serratia
marcescens.

4. BACTERIAL TARGET OF TUMOR
• Obligate anaerobes (e.g Clostridium and
bifidobacterium)
- target the anoxic area of tumor, and inhibit
the growth of tumor.
• Facultative anaerobes (e.g. Salmonella and
Escherichia)
• - identify and penetrate tumors by detecting
and chemotaxising towards small molecule
gradients of serine, aspartate and ribose.

5. BACTERIA AS TUMORICIDAL AGENT
• Clostridium novyi–NT (attenuated clostridium strain) produce
toxicity in tumor even after deletion of genes coding for a
lethal toxin.
• COBALT(combination bacteriolytic therapy)- Clostridium novyi-
NT spores were administered in combination with conventional
chemotherapeutic agents like dolastatin-10, mitomycin C,
vinorelbine and docetaxel.
• Bacillus Calmette Guerin(BCG),the most successful bacterial
agent so far is used specifically for the treatment of superficial
bladder cancer
• Salmonella strain VNP20009-after deletion of two genes msb &
purl results in its complete attenuation.
-VNP20009 has been successfully investigated in phase 1
clinical trials in cancer patients.

6. BACTERIA AS VECTOR FOR GENE
THERAPY AND TUMORICIDAL AGENT
• For delivering anticancer agents, cytotoxic
peptides, therapeutics protein or produrg
converting enzymes.
e.g. Salmonella
• Two reports showed that when transfer of
anti-angiogenic genes (thrombospondin and
endostain) from salmonella, prevent the
formations of new blood vessel and stopped
the nutrient supply in tumor cell.

7. • Attenuated selmonella typhimurium- used to
deliver cytokines(IL-2) locally to liver cancer.
• Various therapeutic proteins, including TNF-alpha
and platelet factor 4 fragment, have been cloned
and expressed in VNP20009.
• Bifidobacterium adolescentis spore administration
via tail vein of tumor-bearing mice resulted in
strong inhibition of angiogenesis.
• Functional TNF- alpha has been cloned and
expressed in C. acetobutylicum.

8. BACTERIA DIRECTED ENZYME
PRODURG THERAPY
• Cytosine deaminase (CD) have been successfully expressed
in C. sporogenes and C. acetobutylicum.
-convert 5-fluorocytosine(5FC) to 5-fluorouracil(5FC).
• Salmonella vector has also been combined with CD and
nitroreductase, and success has been observed in vivo and
it is currently undergoing in phase 1 clinical trials.
• TAPET(Tumor Amplified Protein Expression Therapy) uses
VNP20009 expresses an E.coli CD for preferentially
delivering anti-cancer drug to solid tumor.
• Salmonella + carboxypeptidase G2(enzyme convert
mustard prodrug to DNA cross-linking agent) show
significant results in vivo.

9. BACTERIAL TOXINS FOR CANCER
• Cyclomodulins- bacterial toxins that subvert the host
eukaryotic cell cycle.
E.g. 1. CNF(from E.coli) –cytotoxic necrosis factors, a cell-
cycle stimulator.
- triggers the G1 - S transition and induces DNA
replication.
2. CDTs (cytolethal distending toxins) found in several
Gram- negative bacteria,
-cell-cycle inhibitor
3.Cif from enteropathogenic and enteroheamorrhagic
E.coli,
- block mitosis and inhibit clonal expansion of
lymphocytes.

10. -Bacterial toxins binding to surface antigens
• Pseudomonas exotoxin A inhibit protein synthesis by
catalytically ribosylate EF-2.
• Clostridium perfringens enterotoxic (CPE) investigated
for colon, breast, and gastric cancers due to its
cytotoxic property.
• Botulinum neurotoxin(BoNT) briefly opens tumors
vessels, allowing more effective destruction of cancer
by radiotherapy and chemotherapy.
• Some other toxins undergoing on research are
- alfa toxin from Stapylococcous aureus,
- AC-toxins from Bordetella pertussis
- shiga like toxins
- cholera toxin

11. -BACTERIAL TOXIN CONJUGATED TO LIGAND
• Binding of toxins to cell-binding proteins .e.g
Monoclonol antibodies or growth factors, cause
regression in growth of cancer by targetting them
into the specific sites on cancers.
• For example transferrin-Diphtheria toxin(DT), DT-
epidermal growth factor(EGF) in brain tumor and
metastatic carcinomas and IL4-PE against human
gliboblastoma tumor
• Genetically modified and recombinant toxins e.g
chimeric toxins

12. BACTERIA AS IMMUNOTHERAPEUTIC
AGENTS
• Genetically engineered Attenuated Salmonella
typhimurium expressing murine cytokines (IL-2)
suppress the growth of tumor.
• Xenogenic DNA vaccine encoding tumor endothelial
markers 8(TEM8) carried by attenuated S.typhimurium
has been repoetd to generate TEM8-specific CD8
cytotoxic T-cell response after oral administration.
• C.novyi spores after systematic administration destroy
adjacent cancer cell and trigger an inflammatory
reaction by producing cytokinies such as IL-6, MIP-2, G-
CSF, TIMP-1 and KC…

13. • CANCER VACCINE- A recombinant Listeria
monocytogenes( facultative intracellular
bacteria) vaccine strain expressing nucleoprotein
(NP)from influenza strainA/PR8/34 has shown
great therapeutic potential pre-clinically by
regressing growth off microscopic tumors.
• Bacillus calmette-gurein (BCG-CWS) has been
used as an effective adjuvent for
immunotherapy.

15. PROBLEMS WITH BACTERIAL
THERAPY
• Toxicity
• Infections
• Incomplete tumor lysis
• DNA mutation

16. Conclusion
• Live, attenuated bacteria as antitumor agents
and vectors for gene directed enzyme prodrug
therapy have emerged as potential strategies.
• VNP20009 and TAPET-CD have been
investigated successfully in phase 1 clinical
trial.
• Chemeric toxins are also being investigated as
future toxin-based anticancer therapies.

17. IMPORTANT CLINICAL TRIAL INVOLVING BACTERIAL
INTERVENTION IN CANCER
INTERVENTION CLINICAL PRESENT STATUS DISEASE
(NUMBER TRAIL PHASE CONDITION
COMPOUND)
VNP20009 PHASE 1 COMPLETED ADVANCED
OR METASTATIC
SOLID TUMORS
TAPET-CD HEAD, NECK
PHASE 1 COMPLETED ESOPHAGUS CANCER
Tf-CRM 107 PHASE 1 ONGOING BRAIN ENTRAL NERVOUS
SYSTEM TUMOR
IL4-PE PHASE 1 ONGOING BRAIN ENTRAL NERVOUS
SYSTEM TUMOR
MALIGNANT GILOMA,
GLIBLASTOMA MULTIFORME
IL3-PE PHASE 1 ONGOING ANAPLASTIC ASTROCYTOMA
ANAPLASTIC

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