NCI P01: Molecular Targeted Radionuclide Therapy for Tumor Immunomodulation and Enhancing - PowerPoint Presentation

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NCI P01: Molecular Targeted Radionuclide Therapy for Tumor Immunomodulation and Enhancing Immunotherapy Response

UW TRT

P01

Overview

The First TRT PO1 Awarded

Jamey Weichert, PhD, Prof of Radiology, Medical Physics and Pharmaceutics

To develop a broad mechanistic understanding of the immunomodulatory capacity of TRT and to evaluate TRT as a component of immunotherapy approaches to improve the treatment of immunologically “hot” and “cold” tumors.Understand the differences between TRT and xRT radiation impact on the TME in the context of immunobiologyUnderstand the differences of α, β, and Auger radiation on TME immunobiologyUnderstand and optimize the response-enhancement, T-cell memory induction and resistance properties of combining low-dose TRT with immunotherapy (checkpoint inhibition, immunocytokines, prostate specific DNA-based vaccines)UW P01 Objectives

PO1 Grant Requirements and Comments*NCI Program approval is required for submission of a P01 grant (6 page concept document)You will have to make a presentation to your program team (60 min limit for presentation)Projects (12 pages) and cores (6 pages) must have a common theme and be integrated and dependent on each other (cannot function as separate R01 grants, 12 page summary section required)Program Integration is a separate review categoryAdmin core required and additional cores must serve the majority of projectsStrong leadership and team expertise in all disciplines is extremely important P01s (500-1000+ pages) typically are not funded on the first attempt

.

As with most multi-investigator grants, the

P01

is

only as strong as the weakest component (project, core, investigator)Institutional matching funds are NOT required. (we did get several positive reviewer comments though regarding our $2.1M match)

*

Based on UW experience and JW serving on 2 P01 review cycles

Why a UW P01?Sum of Projects and Cores is Greater than the Parts-SynergyProjects were very Integrated and Dependant on each otherTRT Impact on Tumor MicroenvironmentVectors (NM600, other TRT agents, and isotope types (α/β))Impact of RT on tumor immune infiltrate and host immune system using syngeneic murin tumor modelsUsing imaging-based dosimetry to demonstrate translational principles in companion canine cancer patientsCombining TRT with immune checkpoint inhibitors (efficacy and biomechanism)Combining TRT with Immunocytokines (efficacy and biomechanism)

Combining TRT with DNA-based prostate cancer

vaccines (

efficacy and

biomechanism

)Special New Cores Needed for Success of AimsAdministrative CoreIsotopes and Radiochemistry CoreAdvanced Dosimetry Core

Biostats

Core

Sept 2015 – UW 2020 Letter of Intent (Sondel/Morris/Weichert/ Bednarz)Oct 1, 2016- UW 2020 (2 yr/$500K) Grant initiatedJan 2018 – NIH Biden “Moon Shot” U01 submitted (awarded Sept 2019)June 2018- SNMMI (Philadelphia) Presentations (Hernandez/Grudzinski)June 26, 2018-UW PO1 TRT/Immunomodulation Concept Outline sent to JacekJuly 2018 – First meeting to discuss UW TRT + ImmRx P01 April 2019 – UW TRT + ImmRx P01 presentation at NCI (100 slides in 60 min)May – Sept, 2019 – Biweekly team PO1 meetingsSept 24, 2019 – UW TRT + ImmRx P01 SubmittedMarch 2020 - Summary Statement received April 3, 2020 - Response to Reviewers Comments (15 pages) submitted April-August 2020 - Several Council level meetings/decisions Sept 2020 – UW TRT + ImmRx P01 AwardedUW TRT + ImmRx P01 Timeline

1 Year

UW TRT + ImmRx P01 Project TeamsReinier HernandezRadiochemistry

Joe Grudzinski

Imaging/Dosimetry

Strong Leadership with

a

history of workingtogether.

UW TRT + ImmRx P01 Core TeamsExtremely Strong Core Leadership

UW TRT + ImmRx P01 Management and OversightEC: Project and Core LeadersIAC Chairs/technical advisors

UW TRT + ImmRx External Advisory BoardEAB: Top Leaders in each of the P01 DisciplinesExpertise ProvidedImmuno-Therapy/BiologyRadiation Biology/TherapyTRT Agents/Theranostics Advanced DosimetryIsotope Production

UW TRT + ImmRx P01 Corporate Collaborators

UW TRT + ImmRx P01 – Admin Core AimsAim 1: Provide organizational structure and operational plan needed to achieve overall aims of the P01.Aim 2: Provide scientific oversight of all projects and cores.Aim 3: Coordinate programmatic communication.

Aim 4:

Provide fiscal and grant management services and oversight.

Aim 5:

Assist with and oversee adherence to regulatory and other programmatic policies.

UW TRT + ImmRx P01 – Project 1 AimsObjective: Determine whether TRT can deliver immunomodulatory RT to tumor sites without triggering systemic immune suppression and compare the relative capacity of different TRT agents to achieve this.Aim 1: Characterize the tumor uptake and bio-distribution over time for each therapeutic NM600 chelate(90Y, 177Lu, 225Ac) and for selected alternative TRT vectors (131I-MIBG, 90Y-αGD2 mAb, 225Ac-αGD2

mAb, 131I-NM404, 90Y-

α

SNPR

-Fab, 90Y-PSMA-617)

in syngeneic murine tumor models.Aim 2: Compare the dynamic dose-dependent effects of RT on tumor immune infiltrate and the host

immune system using syngeneic murine tumor models for each therapeutic NM600 chelate and

selected alternative TRT vectors.

Aim 3

:

Demonstrate that the ranges of tumor-absorbed doses necessary for immunomodulation can be

safely translated to larger species by testing each therapeutic NM600 chelate in companion

canines with spontaneous cancers. For this, we will characterize dosimetry, radionuclide biodistribution,

and effect on tumor immune infiltrate and immune cell counts in peripheral blood.

UW TRT + ImmRx P01 – Project 2 AimsObjective: Test whether and to what extent diverse TRT agents can activate a type I interferon response in tumor cells and evaluate the impact of these agents on tumor response to immune checkpoint inhibitors.Aim 1: Determine whether and compare the extent to which TRTs modulate tumor cell immune susceptibility through cGAS/STING-mediated activation of a type I IFN responseAim 2: Evaluate the capacity of TRT and ICI combinations to elicit durable systemic anti-tumor immune response in syngeneic murine tumor models.Aim 3

:

Evaluate whether and how distinct TRT agents (90Y-, 177Lu-, and 225Ac-NM600) may impact the adaptive anti-tumor T cell response in combination with ICIs in syngeneic murine tumor models.

UW TRT + ImmRx P01 – Project 3 AimsObjective: Evaluate the relative capacity of TRT agents to overcome mechanisms that suppress anti-tumor immune response in the tumor microenvironment and test whether TRT may augment response to localized in situ vaccine regimens by overcoming these inhibitory mechanisms.Aim 1: Determine the optimal dose, timing, and sequence of combined in situ vaccination + ICI + TRT + other treatments as needed to enable curative eradication of all cancer in mice with two distinct macroscopic tumor sites and disseminated micro-metastases.Aim 2: Evaluate the cellular and molecular immunotherapeutic mechanisms critical for curative eradication of local and distant 9464D tumors by serial analyses of murine blood, tumor, spleen, and lymph node specimens from Aim 1 studies.

Aim 3

:

Expand the findings of Aims 1 and 2 to other immunologically cold cancers.

Aim 4

: Integrate novel TRT vectors into these in situ vaccine regimens in these model systems to improve the therapeutic window, anti-tumor efficacy, and clinical translatability of this overall strategy.

UW TRT + ImmRx P01 – Project 4 AimsObjective: Determine whether and to what degree TRT agents may facilitate antigen-specific T cell activation and clonal expansion in combination with a tumor-specific vaccine.Aim 1: To determine the effects of different TRT agents on the composition and effector function of immune infiltrating cells in murine prostate cancer models.Aim 2: To determine whether antigen-specific tumor vaccination, when combined with different TRT agents, elicits greater numbers of tumor-specific infiltrating CD8+ T cells.Aim 3:

To determine whether CD8+ T cell infiltration and anti-tumor efficacy elicited with antigen-specific tumor vaccination and TRT treatment are augmented with androgen deprivation.

UW TRT + ImmRx P01 – RPRC Core AimsAim 1: To produce radiochemically pure radionuclides needed as labels of theranostic probesinvestigated in Projects 1 through 4, with special focus on 86Y and 89Zr.Aim 2: To chemically synthesize and subsequently radiolabel precursor synthons of

the

PET/SPECT and theranostic TRT

agents needed for Projects 1 through 4.

Aim 3: To characterize the radioisotopic, radionuclide, radiochemical, and physiologically relevant

aspects of the synthesized radiopharmaceuticals produced for Projects 1 through 4.

Radionuclide Production and Radiochemistry Core

UW TRT + ImmRx P01 – AID Core AimsAim 1: Support investigators in all stages of the imaging and dosimetry process, includingexperimental design, image acquisition optimization, pharmacokinetic profiling and modeling,micro- and macroscopic 3D dose calculations, and treatment response assessment.Aim 2: Develop and apply calibration and quality assurance protocols throughout the quantitativeimaging and dosimetry workflow that limit uncertainties in the critical stages of the process.Aim 3: Establish a radiopharmaceutical treatment planning workflow using rodent cancer modelsand companion animals with spontaneous cancer that will ultimately translate to use in

humans.

Advanced Imaging and Dosimetry Core

Superior Rating

: Provides exceptional services encompassing truly unique,

innovative approaches and cutting-edge technology, andOffers exceptional resources and highly-experienced leadership (“Honors rating and only a few cores will qualify for this rating”)

UW TRT + ImmRx P01 – Biostats & Bioinfo Core AimsAim 1: To provide support and expertise in biostatistical methods in the design of research studies, dataanalysis and inference, publication of research, and dissemination of research findings to thescientific community.Aim 2: To provide support and expertise in bioinformatics analysis, interpretation of deep TCRsequencing, RNAseq, and single cell sequencing data, and dissemination of research findings tothe scientific community.

Aim 3:

To develop a P01-wide database in collaboration with the Administration Core and to support

research data management for the P01 Projects to enhance rigor and transparency of P01-

generated data.

Biostats and Bioinformatics Core

UW TRT + ImmRx P01 Project and Core IntegrationProject 1: MTRTs for dosimetry-guided immunomodulationProject 2: MTRT to enhance tumor immune susceptibility and response to checkpoint inhibitorsProject 3: MTRT to overcome immune suppression and diversify T cell response after in situ vaccineProject 4:

MTRT with tumor-specific vaccine to stimulate and expand T-cell activation

Dosimetry and Imaging Core

Radiopharmaceutical Production Core

Administrative Core

Biostatistics/Bioinformatics Core

A product that is greater than the sum of its parts

Program Integration

Common theme

Data sharing between projects

Cores support at least 2 projects

Regular communication among

investigators

Highly Integrated

:

Synergy ,

data from one project guides another

Questionsjweichert@uwhealth.org