Structure of Talk

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Structure of Talk

• Background
• Clinical Trial in Locally Recurrent PC
• Clinical Trials in Newly-Diagnosed PC
• Imaging Gene Expression in Prostate

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80 Gy?
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Ways To Increase Effectivenessof Radiation
TherapyPhysical Means

• Increase RT dose (turn up the dial)
• Advantages
• Simple concept and straightforward
• It works!!
• Disadvantages
• Limit to dose that can be delivered due to normal
  tissue damage
• No systemic effect
• CANT exploit our vast understanding of the
  molecular basis of human cancer

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Ways To Increase Effectivenessof Radiation
TherapyBiological-Chemical Means

• Increase Effectiveness of RT dose (turn up the
  gain)
• Advantages
• Potential therapeutic gain far exceeds dose
  escalation
• 80 Gy x 1.3 104 Gy
• Possible systemic effects
• CAN exploit our vast understanding of the
  molecular basis of human cancer
• Disadvantages
• Most are still investigational (unproven)

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A Novel Three-Pronged Approach
Oncolytic Viral Therapy
Suicide Gene Therapy
Radiation Therapy
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Theoretical Advantages of Replication-Competent
Adenoviruses as Cancer Gene Therapy Vectors

• In contrast to replication-defective adenoviruses
  (Rep-Def), replication-competent adenoviruses
  (Rep-Com) are cytopathic. Thus, the vector
  itself generates an anti-tumor effect.

• Owing to their ability to replicate,
  replication-competent Ads result in much higher
  transgene expression per cell. This results in
  greater therapeutic gene expression per viral
  dose.

• Replication-competent (RC) adeno-viruses have the
  potential to spread throughout the tumor thereby
  infecting a greater number of tumor cells.

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Locally Recurrent Prostate Cancer
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• E1 region
• wt E1A gene
• 55 kDa E1B-deleted
• Contains bCD/wt HSV-1 TK fusion gene under
  control of CMV promoter in E1 region
• E3 region
• No E3 genes

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• Loss of libido/ED
• Hot flushes/sweats
• Fatigue/muscle weakness
• Bone loss/bone fractures
• Anemia
• Weight Gain
• Depression

• Not curative

• Significant morbidity

Gene Therapy?
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Clinical Trial 1Inclusion Criteria

• Biopsy-proven local recurrence of prostate cancer
  at least one year after completion of definitive
  radiotherapy.
• Unequivocally rising PSA on at least 3 separate
  occasions (ASTRO BF) but lt 20 ng/mL.
• No evidence of metastatic disease.
• No prior chemotherapy or hormone therapy.

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Clinical Trial 1Design- Classical Dose Escalation
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Clinical Trial 1Short-Term Results

• Toxicity
• The gene therapy was associated with low toxicity
• 94 of AEs were mild (grade 1) to moderate (grade
  2)
• Pain at injection site (100)
• Hematologic suppression (56, grade 1/2
  lymphopenia)
• Transaminitis (25, all grade 1)
• Flu-like symptoms (38, all grade 1)
• 6 grade 3
• 1 event each of lymphopenia neutropenia
• 4 events of hyperglycemia
• Efficacy
• There were encouraging signs of efficacy
• PSA declines (50 showed gt 25 PSA decline)
• Prostate biopsy

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87 years 6 years post GT PSA 10.1
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Clinical Trial 15-Year Results

• When considering all evaluable patients (n 14),
  the gene therapy
• Resulted in a doubling of the mean PSADT (17 to
  31 months, p 0.014).
• There appeared to be a dose effect
• Lower Ad dose levels- 3 of 8 (38)
• Highest Ad dose level- 5 of 6 (83)
• Delayed the onset of salvage AST by an average of
  2.1 years (all patients) and 2.6 years (highest
  Ad dose).

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Clinical Trial 15-Year Results

• Given that the adenovirus was eliminated in all
  patients by Day 76, what is the basis for the
  observed lengthening of PSADT that in some
  patients persisted for over 6 years?
• We believe the most likely explanation is that
  the gene therapy induced long-lasting anti-tumor
  immunity in some patients.

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Comparison of Our Data to U of M
Experience Patients With PSA Relapse After
Conformal Radiotherapy
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Comparison of Our Data to U of M
Experience Patients With PSA Relapse After
Conformal Radiotherapy
1Sandler, H et al., IJROBP 48 629 - 633 (2000).
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Hypothesis

• When applied in the setting of a rising PSA after
  definitive therapy, replication-competent
  adenovirus-mediated suicide gene therapy followed
  by standard of care will improve overall and
  cause-specific survival relative to standard of
  care alone.

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Immunological Endpoints
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Newly-Diagnosed Prostate Cancer
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Median Follow-up of 5.1 2.0 years
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Clinical Trials 2 3 Inclusion Criteria

• Biopsy-proven localized adenocarcinoma of the
  prostate with significant risk for failure
• Clinical Stages T1c through T4 and
• Gleason score ? 7 or PSA gt 10 ng/mL and ? 50
  ng/mL
• No evidence of metastatic disease
• No prior radiation therapy or chemotherapy
• Prior hormone therapy was allowed

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Clinical Trials 2 3Patient Baseline
Characteristics
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Clinical Trials 2 3Short-Term Results

• Toxicity
• The gene therapy was associated with low toxicity
• 94 of AEs were mild (grade 1) to moderate (grade
  2)
• Pain at injection site (100)
• Hematologic suppression (92 vs. 56 grade 1/2
  lymphopenia)
• Transaminitis (42 vs. 25 all but one grade 1)
• Flu-like symptoms (25 vs. 38 all grade 1)
• No significant increase in GU GI toxicities
  relative to RT
• Efficacy
• There were encouraging signs of efficacy
• Faster that expected PSA declines
• Post-treatment prostate biopsy

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Clinical Trials 2 3Most Frequent Adverse Events
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Clinical Trials 2 3Short-Term Results

• Toxicity
• The gene therapy was associated with low toxicity
• 94 of AEs were mild (grade 1) to moderate (grade
  2)
• Pain at injection site (100)
• Hematologic suppression (92 vs. 56 grade 1/2
  lymphopenia)
• Transaminitis (42 vs. 25 all but one grade 1)
• Flu-like symptoms (25 vs. 38 all grade 1)
• No significant increase in GU GI toxicities
  relative to RT
• Efficacy
• There were encouraging signs of efficacy
• Faster that expected PSA declines
• Post-treatment prostate biopsy

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Clinical Trials 2 3Summary of Post-T Prostate
Biopsy Results
Positive Negative
All Patients
Expected 50 50
HFHS (n 23) 26 (p 0.04)
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Possible Explanations for Differential Effect
Between Intermediate- vs. High-Risk Disease

• High-grade prostate cancer is more infiltrative
  (geographical)
• Escalate the adenovirus dose (5 x 1012 vp)
• Optimize adenovirus distribution at time of
  injection
• High-grade prostate cancer is less infectable by
  adenovirus (biological)
• Develop adenoviruses that can infect high-grade
  prostate cancer independent of CAR.

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Possible Explanations for Differential Effect
Between Intermediate- vs. High-Risk Disease

• High-grade prostate cancer is more infiltrative
  (geographical)
• Escalate the adenovirus dose (5 x 1012 vp).
• Optimize adenovirus distribution at time of
  injection.
• High-grade prostate cancer is less infectable by
  adenovirus (biological)
• Develop adenoviruses that can infect high-grade
  prostate cancer independent of CAR.

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Hypothesis

• Replication-competent adenovirus-mediated suicide
  gene therapy will improve the outcome of IMRT
  relative to IMRT alone in newly-diagnosed
  intermediate-risk prostate cancer.

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Summary of Gene Therapy Clinical Trials

• We have completed 3 prostate cancer clinical
  trials (2 different settings)
• The gene therapy is SAFE
• The gene therapy was able to impact two
  clinical endpoints (PSADT prostate biopsy) that
  have significant prognostic power for disease
  progression and prostate cancer-specific
  mortality.

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Imaging Gene Expression in the Prostate
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Questions That Can Be Answered With Non-Invasive
Imaging

• It allows us to
• Assess the quality of the adenovirus injection
  (albeit gt 1 days after the Ad injection).
• Determine the level and volume of therapeutic
  gene expression in the prostate, which can be
  correlated with clinical outcome.
• Optimize the deposition of adenovirus in the
  target organ.
• Determine the whole body distribution of the
  adenovirus.
• With serial imaging, determine the persistence of
  therapeutic gene expression, which can be
  correlated with clinical outcome.

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1012 vp Ad injected into right apex only
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Questions That Can Be Answered With Non-Invasive
Imaging

• It allows us to
• Assess the quality of the adenovirus injection
  (albeit gt 1 days after the Ad injection).
• Determine the level and volume of therapeutic
  gene expression in the prostate, which can be
  correlated with clinical outcome.
• Optimize the deposition of adenovirus in the
  target organ.
• Determine the whole body distribution of the
  adenovirus.
• With serial imaging, determine the persistence of
  therapeutic gene expression, which can be
  correlated with clinical outcome.

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Base
Fused CT/SPECT Images
0.0 mm
Right
Left
15.0 mm
Max
24.0 mm
36.0 mm
39.0 mm
Apex
Volume of gene expression 6.9 cc (15 of
prostate volume) Maximum width of gene expression
is 1.5 cm from apex.
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Questions That Can Be Answered With Non-Invasive
Imaging

• It allows us to
• Assess the quality of the adenovirus injection
  (albeit gt 1 days after the Ad injection).
• Determine the level and volume of therapeutic
  gene expression in the prostate, which can be
  correlated with clinical outcome.
• Optimize the deposition of adenovirus in the
  target organ.
• Determine the whole body distribution of the
  adenovirus.
• With serial imaging, determine the persistence of
  therapeutic gene expression, which can be
  correlated with clinical outcome.

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Questions That Can Be Answered With Non-Invasive
Imaging

• It allows us to
• Assess the quality of the adenovirus injection
  (albeit gt 1 days after the Ad injection).
• Determine the level and volume of therapeutic
  gene expression in the prostate, which can be
  correlated with clinical outcome.
• Optimize the deposition of adenovirus in the
  target organ.
• Determine the whole body distribution of the
  adenovirus.
• With serial imaging, determine the persistence of
  therapeutic gene expression, which can be
  correlated with clinical outcome.

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Questions That Can Be Answered With Non-Invasive
Imaging

• It allows us to
• Assess the quality of the adenovirus injection
  (albeit gt 1 days after the Ad injection).
• Determine the level and volume of therapeutic
  gene expression in the prostate, which can be
  correlated with clinical outcome.
• Optimize the deposition of adenovirus in the
  target organ.
• Determine the whole body distribution of the
  adenovirus.
• With serial imaging, determine the persistence of
  therapeutic gene expression in the prostate,
  which can be correlated with clinical outcome.

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Kinetics of Gene Expression in ProstateFused
CT/SPECT Images
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Kinetics of Gene Expression in ProstateROI
Analysis
2
Day
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Gene Expression Volume in Prostate1 x 1012 vp
Injected in 1 cc
1GEV- Gene Expression Volume
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SPECT Imaging of Adenovirus-Mediated Gene
Expression In Prostate Cancer
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Questions That Can Be Answered With Non-Invasive
Imaging

• It allows us to
• Assess the quality of the adenovirus injection
  (albeit gt 1 days after the Ad injection).
• Determine the level and volume of therapeutic
  gene expression in the prostate, which can be
  correlated with clinical outcome.
• Optimize the deposition of adenovirus in the
  target organ.
• Determine the whole body distribution of the
  adenovirus.
• With serial imaging, determine the persistence of
  therapeutic gene expression in the prostate,
  which can be correlated with clinical outcome.

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Future Plans

• Prostate Cancer (2007/2008)
• RC Phase 2/3 Newly Diagnosed Trial
• RC Phase 2/3 Locally Recurrent (Salvage) Trial
• Pancreatic Cancer (2007)
• Phase 1 (treated 5 patients thus far)
• Brain Cancer (2008)
• Phase 1

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Clinical Research Jae Ho Kim, M.D.,
Ph.D. Steve Brown, Ph.D. Ben Movsas, M.D. Ken
Barton, Ph.D. Ibrahim Aref, M.D. Vladimir
Ternovoi, M.D. Rad Onc Physicians Yingshu
Zhang Shidong Li, Ph.D. Hui Peng Hans Stricker,
M.D. Farzan Siddiqui, M.D. James Peabody,
M.D. Dell Paielli Jan Pegg, R.N. Ken Rogulski,
Ph.D. Mei Lu, Ph.D. Yunjie Xie, M.D.,
Ph.D. K.C. Karvelis, M.D. Sang Hie Kim,
Ph.D. M. DePeralta-Venturina, M.D. Andy
Kolozsvary Adnan Savera, M.D. Summer Xia Janice
Clark Mark Wing Henry Wong, M.D. Sweaty
Koul PANC Team Don Tyson