VACCINE ADJUVANTS, TO ENHANCE THE ACTIVITY OF WEAK IMMUNOGENS, MAY FUNCTION IN SEVERAL WAYS:

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VACCINE ADJUVANTS, TO ENHANCE THE ACTIVITY OF
WEAK IMMUNOGENS, MAY FUNCTION IN SEVERAL WAYS

• 1 Depot for vaccine (prolonging the time period
  of antigen presentation)
• 2 As a means to change the character number
• activation state of APCs at the vaccination
  site
• 3 Tool to alter the immunologic pathway (protein
  presentation and process)

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ADJUVANTS IN CANCER VACCINES

• Keyhole limpet hemocyanin (KLH)
• GM-CSF
• IMIQUIMOD
• IL-2 friend or foe?

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KLH

• Work in mice suggested that it had an
  adjuvant-like effect in DC vaccination
• (Timmerman JM J.Jummol 2000)
• In vitro studies in human cells supported such an
  effect
• (Osugi Y. Blood 2002)
• A number of groups have used there observations
  to justify inclusion of KLH in experimental
  protocols
• (Azima T. Int J. Oncol. 2002, Geiger JD
  Cancer Res 2001, Hernando JJ Cancer Immunol
  Immunoth 2002, Rains N Hepatogastroenterol 2001,
  Timmerman JM Blood 2002)

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GM-CSF

• GM-CSF as a systemic adjuvant in a phase II
  prostate cancer vaccine trials (SIMMONS SJ
  Prostate 1999) ineffective (?)
• GM-CSF trasduced tumor vaccines release
  GM-CSF.induce the differentiation and
  proliferation of huge number of DC at the site of
  vaccine injection. Phase I/II are promising in
  prostate cancer (PARDOLL DM iSBTc Proceeding
  Alexandria Nov 2005)
• GM-CSF can modulate the migratory phenotype of
  vaccine-induced T-cells by enhancing CXCR3
  expression
• (KEILHOLZ V iSBTC Proceeding Alexandria Nov
  2005)

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IMIQUIMOD (ALDARA)

• A TOLL-LIKE receptor-7 Ligand (TLR7L)
• Therapy of genital warts and cutaneous
  malignancies (and premalignancies)
• Basal Cell Carcinoma
• Melanoma in situ (Ray CM Int. J.Derm 2005)
• Case report cutaneous metastases of melanoma
  treated with IMIQUIMOD, PEG-INTRON and IL-2
  PRgt90
• (Loquai C. Hautarzt 2004)
• Priming of CTL by transcutaneous peptide
  immunization with IMIQUIMOD (Rechtsteiner G
  J.Immunol 2005)

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IMIQUIMOD (ALDARA)

• IMIQUIMOD enhances the anti-melanoma effects of a
  recombinant Listeria monocytogenes vaccine (Craft
  N. J.Immunol 2005)
• RESIQUIMOD produce an immunoresponse with a
  10-fold reduced dose compared with IMIQUIMOD
  (Thomsen LL Vaccine 2004)
• Injection of immature DC into adjuvant-treated
  skin (with IMIQUIMOD) obviates the need for ex
  vivo maturation 111Indium labeled DC migration
  capacity (Mairs and Gilboa E J.Immunol 2003)

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IMIQUIMOD (ALDARA)

• GENE PROFILING OF BASAL CELL CARCINOMA TREATED
  WITH IMIQUIMOD REVEALS KEY SIGNATURES OF TUMOR
  REJECTION Panelli M. iSBTc Proc. Alexandria
  (USA) Nov.2005
• Transcriptional events from 36 pts enrolled in
  double blind (placebo controlled) group study
• cDNA microarrays of BCC samples treated with q12
  time 4 days schedule identified 637 genes among
  early and late
• - 98 genes were associated with IFN-associated
  patterns
• - 539 were classified as IMIQUIMOD specific
  genes and were similar to the patterns identified
  in tumor treated with IL-2 (common pathway
  necessary for cancer rejection)

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IL-2 Main Lymphocyte activating Factor
FRIEND
FOE
or
TOLERANCE, NOT IMMUNITY, CRUCIALLY DEPENDS ON
IL-2
MALEK TR, BAYER AL NAT REV IMMUNOL, 2004
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pro IL-2

• Clinical responses in melanoma and renal cell
  carcinoma
• NK and T-cell activation
• Rescue of defects produced by local tumor
  immunosuppression in TIL and APC (Zier 96,
  Whiteside 98, Kuss 2002, De Paola 2003, Riccobon
  2004)
• Induction of the capacity of CD8 T cells to home
  to the site of action (Andersen 2005)
• Intralesional administration induces clinical
  responses (Ridolfi 2002,Radny 2003)
• Adjuvant in cancer vaccines(?) (Panelli 2000,
  Shimizu 2000, Andersen 2001, Stift 2003,
  Maztalerz 2003, Escobar 2005)
• Increased frequency of IFN-gamma producing memory
  cell in HIV infected patients (Kuekrek 2005)

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pro IL-2
a genomic-and proteomic-based hypothesis of
eclectic effects of systemic IL-2 administration
in the context of melanoma-specific
immunization Panelli MC et al Cell Tissue
Organs 2004
Changes in transcriptional profile of melanoma
metastases induced by IL-2

• Monocyte activation into mature APC
• Production of chemo-attractans that recruit
  immuno-cells
• Different individuals respond differently to
  IL-2 in relation to the polymorphism of their
  IL-2Receptor (or polymorphisms of promoter region)

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pro IL-2
Molecular Pathways of IL-2
JIN et al - iSBTc Proceedings Nov.2005 Alexandria
(USA)

• Evaluation in PBMC of 47 donors
• after IL-2 stimulation
• IL-2 induces activation in 1690 genes
• Differencies from Caucasians (784) compared to
  Chineses (458)

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pro IL-2
IL-2 restored radiation-and surgery-induced
T-cell defects in HNSCC patients Herold- Mende C
et al Adv Otorhinolaring. 2005

• Hypothesis of explanations by T.Whitesite
• Up regulation of interactions between DC and
  T-cells
• Elimination of activated CD4CD25 suppressor
  cells by RT
• Protection of CD4 precursors from RTdamage
• Normalization of T-cell turnover with a greater
  number of specific CD8 in the central
  memory/effector cell compartments
• Greater sensitivity of tumor cells expressing low
  affinity IL-2R to the RT low tumor burden

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contra IL-2
IL-2
Exhaustion of DC
induction of
CTLA-4
IL-2 production
inactivation
T-cell
DC
activation of
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contra IL-2
Concurrent administration of low dose IL-2 with
melanoma peptide vaccine induces a lower number
of activated T-cell compared to a delayed
schedule Slingluff CL JCO 2004
Tumor regression and autoimmunity in patients
treated with anti-CTLA-4 and IL-2 a phase I/II
study 36 pts 8OR (22) 3CR 5PR No
evidence of synergistic effect Maker AV,
Rosenberg SA ANN SURG ONCOL 2005
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contra IL-2

• Mantains T-reg survival
• T-reg cells require IL-2 from Helper T cells for
  the maintenance of the high affinity IL-2R and
  Foxp3 expression
• IL-2 controls the frequency of the T-reg cell
  population and is essential for their function
  and competitive fitness in periphery
• The T-reg cells suppress the function of effector
  cells in vivo
• IL-2 and lymphopenia are primary modulators of
  T-reg
• Fontenot JD et al Nat Immunol 2005
• Rudensky A et al 2005
• La Rosa et al Eur J Immunol 2004

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IL-2 AND VACCINES
FRIEND OR FOE

• Attention to T-reg lymphocytes
• Low dose chemotherapy ?
• Anti-CTLA-4 ?
• The TIMING of the schedule is DECISIVE
• and moreover
• Which dose?
• IL-7 (IL-15?) expands CD4 and CD8 not T-reg!

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If only were all so simple. If only there were
evil people some-where insidiously committing
evil deeds, and it were necessary only to
separate them from the rest of us and destroy
them. But the line dividing good and evil cuts
through the heart of every human being, and who
is willing to destroy his own heart? Da
Arcipelago Gulag di Alexander
Solzhenitsyn Ichim CV J Transl Med
2005