Radiation Countermeasures: Radiation Countermeasures: Interfacing with Clinical Interfacing with Clinical

OncologyOncologyPaul Okunieff, MD

CMCR Steering Committee ChairCBARMFI Principal Investigator

OVERVIEW OF PROGRESS SINCE 2005OVERVIEW OF PROGRESS SINCE 2005

Can radiation side effects be mitigated?Can radiation side effects be mitigated?• Many new agents and mechanisms Many new agents and mechanisms (there were none in (there were none in

2005)2005)• Improved supportive measures Improved supportive measures (those used before 2005 might (those used before 2005 might

have been detrimental)have been detrimental)• New industry base New industry base (mostly micropharma) (mostly micropharma) Implications: The harmful effects of therapeutic radiation Implications: The harmful effects of therapeutic radiation

may be “removed” after the cancer is controlled.may be “removed” after the cancer is controlled.Can biodosimetry be used to perform mass Can biodosimetry be used to perform mass

screening?screening?• Many new technologies for genotoxicity measurement Many new technologies for genotoxicity measurement • Many new technologies and biological markers for metabolic Many new technologies and biological markers for metabolic

responseresponseImplications: The immediate response of tumor following Implications: The immediate response of tumor following

might be monitored to assess response and impact of might be monitored to assess response and impact of combinations with radiation modifying agentscombinations with radiation modifying agents

OVERVIEW OF PROGRESS SINCE 2005OVERVIEW OF PROGRESS SINCE 2005

Can radiation side effects be mitigated?Can radiation side effects be mitigated?Many new agents and mechanisms Many new agents and mechanisms (there were none in 2005)(there were none in 2005)Improved supportive measures Improved supportive measures (those used before 2005 might (those used before 2005 might have been detrimental)have been detrimental)New industry base New industry base (mostly micropharma) (mostly micropharma) Implications: The harmful effects of therapeutic radiation Implications: The harmful effects of therapeutic radiation

may be “removed” after the cancer is controlled.may be “removed” after the cancer is controlled.

Can biodosimetry be used to perform mass Can biodosimetry be used to perform mass screening?screening?

Many new technologies for genotoxicity measurement Many new technologies for genotoxicity measurement Many new technologies and biological markers for metabolic Many new technologies and biological markers for metabolic

responseresponseImplications: The immediate response of tumor following Implications: The immediate response of tumor following

might be monitored to assess response and impact of might be monitored to assess response and impact of combinations with radiation modifying agentscombinations with radiation modifying agents

CMCR and most similar grants and contracts from NIAID and BARDA specifically forbid employing

any of the funding they provide for therapeutic testing of cancer patients (with very specific

individually approved exceptions).

FDA: cancer patients are not considered a model of a radiation bioterror or a nuclear event

FDA Requirements:FDA Requirements:1.1.Mitigation in at least 1 animal model (logically requiring primates)Mitigation in at least 1 animal model (logically requiring primates)

2.2.Sufficient benefit to be worthwhile in an animal model for a specific Sufficient benefit to be worthwhile in an animal model for a specific scenario scenario (fallout, ground shine, blast, inhalation, combined injury, dirty bomb…)(fallout, ground shine, blast, inhalation, combined injury, dirty bomb…)

3.3.Proven mechanism of action Proven mechanism of action

4.4.Similarity of action between species tested and manSimilarity of action between species tested and man

5.5.Safety in an otherwise healthy populationSafety in an otherwise healthy population

1.1.Mitigation in at least 1 animal model (logically requiring primates)Mitigation in at least 1 animal model (logically requiring primates)

2.2.Sufficient benefit to be worthwhile in an animal model for a specific Sufficient benefit to be worthwhile in an animal model for a specific scenario scenario (fallout, ground shine, blast, inhalation, combined injury, dirty bomb…)(fallout, ground shine, blast, inhalation, combined injury, dirty bomb…)

3.3.Proven mechanism of action Proven mechanism of action

4.4.Similarity of action between species tested and manSimilarity of action between species tested and man

5.5.Safety in an otherwise healthy populationSafety in an otherwise healthy population

The money spent so far in the CMCR and other The money spent so far in the CMCR and other NIAID, DARPA, and BARDA objectives have NIAID, DARPA, and BARDA objectives have been rewarded by been rewarded by substantial practical progress substantial practical progress but no approved agentsbut no approved agents. Agencies looking for a . Agencies looking for a

better partnership with FDA better partnership with FDA

State of CMCR Drug Development:State of CMCR Drug Development:

Organ Specific:Organ Specific:The mechanisms leading to acute The mechanisms leading to acute and late organ and late organ dysfunctiondysfunction overlap, overlap, but are distinctly different.but are distinctly different.Different mitigation for different Different mitigation for different organs: CCOP researchorgans: CCOP research

Time Dependant: Time Dependant: The mechanisms leading to acute The mechanisms leading to acute organ organ damagdamage are different than e are different than those causing long term progressive those causing long term progressive damagedamageDifferent mitigation at different times Different mitigation at different times after exposure: CCOP and after exposure: CCOP and Survivorship researchSurvivorship research

Exposure type (eg inhalation):Exposure type (eg inhalation):If marrow is not exposed lethal If marrow is not exposed lethal injury can take months or yearsinjury can take months or yearsTime bomb: survivorship research Time bomb: survivorship research

The needed agents The needed agents are time, dose, are time, dose, radiation type and radiation type and organ specificorgan specific

University of Rochester (P Okunieff)This CMCR agent mitigates GI syndrome with survival up to 16 Gy (Control lethal dose (LD50) ≈ 8 Gy).

D68 Mitigates Gastrointestinal Syndrome

0

20

40

60

80

100

120

0 10 20 30 40Days after Irradiation

Surv

ival (%

) 12 Gy

D68 120 mg/kg/d after 12 Gy

Drug given daily beginning shortly after radiation

• Curcumin was effective at reduction of cutaneous syndromes Curcumin was effective at reduction of cutaneous syndromes but was less effective and potential disadvantageous for GI but was less effective and potential disadvantageous for GI syndromesyndrome

• Curcumin is poorly absorbed and varies greatly between Curcumin is poorly absorbed and varies greatly between individuals and with different dietsindividuals and with different diets

• D68 overcomes some of those limitations (absorption and GI)D68 overcomes some of those limitations (absorption and GI)

• D68 is very relevant to cancer researchD68 is very relevant to cancer research

• GI toxicity limits our ability to treat many abdominal GI toxicity limits our ability to treat many abdominal tumorstumors

• Curcumin is expected to improve tumor responseCurcumin is expected to improve tumor response

• Human experience with agent would help CMCR missionHuman experience with agent would help CMCR mission

Pre-Pre-radiationradiation

6 months6 months50 Gy50 Gy

(10 fractions) (10 fractions)

7 years7 years

h-EsA is another agent that does not h-EsA is another agent that does not appear to deleteriously affect tumor appear to deleteriously affect tumor control but powerfully mitigates lung control but powerfully mitigates lung toxicitytoxicity

The implications for improving the The implications for improving the safety and therefore the utility of focal safety and therefore the utility of focal lung irradiation is substantiallung irradiation is substantial

C57BL/6 mouse

H-EsA

Range of Devices and Agents being Developed by CMCR:Range of Devices and Agents being Developed by CMCR:

Triage: exposed vs. not-exposedProteomicGenomic / genotoxicityMetabolomic

Simple (dipstick) vs. Advanced technology

Dosimetry: Actual physical dose received (whole vs. partial body)Genotoxicity assays Physical chemistry methods (free electrons in teeth, nails)

Mitigation: Agents given after exposure that prevent late deathsExample: delayed death due to lung or renal failure

Treatment: Agents that reduce severity of existing problemsAntibiotics, growth factors, …

Epidemiology: Tools to allow long-term evaluation of survivorsCritical for agent development and validation but requires useful interventions and technologies as defined above

Range of Devices and Agents that Need to be Developed:Range of Devices and Agents that Need to be Developed:

Triage: exposed vs. not-exposedProteomicGenomic / genotoxicityMetabolomic

Simple (dipstick) vs. Advanced technology

Dosimetry: Actual physical dose received (whole vs. partial body)Genotoxicity assays Physical chemistry methods (free electrons in teeth, nails)

Mitigation: Agents given after exposure that prevent late deathsExample: delayed death due to lung or renal failure

Treatment: Agents that reduce severity of existing problemsAntibiotics, growth factors, …

Epidemiology: Tools to allow long-term evaluation of survivorsCritical for agent development and validation but requires useful interventions and technologies as defined above

All of these have potential correlates with clinical oncology

Clinical oncology studies would serve the mission of both cancer research and mitigation research

• improve access to agents (virtual stockpile)

• gain comfort and experience with the agents and technologies

Goal of this workshop:Goal of this workshop:

We want to be able to say in 2015 that the We want to be able to say in 2015 that the money spent by the CMCR and other NIAID, money spent by the CMCR and other NIAID, DARPA, and BARDA objectives have been DARPA, and BARDA objectives have been rewarded by substantial peacetime medical rewarded by substantial peacetime medical

advancements -- in addition to supplying agents advancements -- in addition to supplying agents for the Strategic National Stockpilefor the Strategic National Stockpile

AFRRI: Armed Forces AFRRI: Armed Forces Radiation Research Radiation Research

InstituteInstitute

Some comments about AFRRISome comments about AFRRI

1.1. History of excellence in radiation biology, with pioneering work in History of excellence in radiation biology, with pioneering work in radiation protectors, growth factor radiomodification, biodosimetry, and radiation protectors, growth factor radiomodification, biodosimetry, and combined injurycombined injury

2.2. Major impact coordinating national meetings, modeling emergency Major impact coordinating national meetings, modeling emergency scenarios, publications for mass casualty events…scenarios, publications for mass casualty events…

3.3. Probably the best resourced radiobiological lab in the world:Probably the best resourced radiobiological lab in the world:• Ultra high dose rate CobaltUltra high dose rate Cobalt• ReactorReactor• Near GLP primate lab geared to do radiobiology studiesNear GLP primate lab geared to do radiobiology studies

4.4. Recent funding increases for both badly needed infrastructure updates Recent funding increases for both badly needed infrastructure updates and researchand research

5.5. However, their mission and resources, like the CMCR, permits little However, their mission and resources, like the CMCR, permits little translation of their work for cancer patientstranslation of their work for cancer patients

1.1. History of excellence in radiation biology, with pioneering work in History of excellence in radiation biology, with pioneering work in radiation protectors, growth factor radiomodification, biodosimetry, and radiation protectors, growth factor radiomodification, biodosimetry, and combined injurycombined injury

2.2. Major impact coordinating national meetings, modeling emergency Major impact coordinating national meetings, modeling emergency scenarios, publications for mass casualty events…scenarios, publications for mass casualty events…

3.3. Probably the best resourced radiobiological lab in the world:Probably the best resourced radiobiological lab in the world:• Ultra high dose rate CobaltUltra high dose rate Cobalt• ReactorReactor• Near GLP primate lab geared to do radiobiology studiesNear GLP primate lab geared to do radiobiology studies

4.4. Recent funding increases for both badly needed infrastructure updates Recent funding increases for both badly needed infrastructure updates and researchand research

5.5. However, their mission and resources, like the CMCR, permits little However, their mission and resources, like the CMCR, permits little translation of their work for cancer patientstranslation of their work for cancer patients

Some comments about AFRRISome comments about AFRRI

1.1. Very interested in collaborationsVery interested in collaborations

• Internal grant program reaches out to CMCR leadership as outside Internal grant program reaches out to CMCR leadership as outside reviewersreviewers

• Collaborate with civilian researchers on multidisciplinary projectsCollaborate with civilian researchers on multidisciplinary projects

• Collaborate with national labsCollaborate with national labs

2.2. BiodosimetryBiodosimetry

• Multi-component assays using routine technologies, hematological Multi-component assays using routine technologies, hematological and chemistryand chemistry

3.3. Mitigation agent testing and discoveryMitigation agent testing and discovery• Anti-apoptotic agents, NFKB, AKT, and growth factorsAnti-apoptotic agents, NFKB, AKT, and growth factors• Anti-oxidants (Amiphostine)Anti-oxidants (Amiphostine)

1.1. Very interested in collaborationsVery interested in collaborations

• Internal grant program reaches out to CMCR leadership as outside Internal grant program reaches out to CMCR leadership as outside reviewersreviewers

• Collaborate with civilian researchers on multidisciplinary projectsCollaborate with civilian researchers on multidisciplinary projects

• Collaborate with national labsCollaborate with national labs

2.2. BiodosimetryBiodosimetry

• Multi-component assays using routine technologies, hematological Multi-component assays using routine technologies, hematological and chemistryand chemistry

3.3. Mitigation agent testing and discoveryMitigation agent testing and discovery• Anti-apoptotic agents, NFKB, AKT, and growth factorsAnti-apoptotic agents, NFKB, AKT, and growth factors• Anti-oxidants (Amiphostine)Anti-oxidants (Amiphostine)

Optimizing future success:Optimizing future success:

1.1. Low hanging fruitLow hanging fruit: : agents already know to be safe and already agents already know to be safe and already subject to substantial human testingsubject to substantial human testing

2.2. New (creative) agents will have a proposed mechanism:New (creative) agents will have a proposed mechanism: mechanisms component of the animal rule may delay approval, mechanisms component of the animal rule may delay approval, and safety will be unknownand safety will be unknown

3.3. Challenge regarding mechanismChallenge regarding mechanism: : mechanism is not a critical mechanism is not a critical part of most FDA approvals (it is supportive data)part of most FDA approvals (it is supportive data)

1.1. Low hanging fruitLow hanging fruit: : agents already know to be safe and already agents already know to be safe and already subject to substantial human testingsubject to substantial human testing

2.2. New (creative) agents will have a proposed mechanism:New (creative) agents will have a proposed mechanism: mechanisms component of the animal rule may delay approval, mechanisms component of the animal rule may delay approval, and safety will be unknownand safety will be unknown

3.3. Challenge regarding mechanismChallenge regarding mechanism: : mechanism is not a critical mechanism is not a critical part of most FDA approvals (it is supportive data)part of most FDA approvals (it is supportive data)

Potential for agents to become better understood Potential for agents to become better understood and validated if used in a cancer population. The and validated if used in a cancer population. The

FDA’s acceptance of toxicity is naturally higher in FDA’s acceptance of toxicity is naturally higher in cancer patients than it would be in a healthy cancer patients than it would be in a healthy

populationpopulation