The Optimistic Urologic Pathologist: Select innovations in diagnosis,

prognosis, and treatmentDavid G. Bostwick, MD, MB

Innovations in Urologic Pathology: 2020

• Digital Pathology• 3D Reconstruction• Immunotherapy

OLD

NEW

US Food and Drug Administration Approval of Whole Slide Imaging

for Primary DiagnosisEvans A, et al. Arch Pathol Lab Med 2018; 142:1383

• “April 12, 2017 marked a significant day in the evolution of digital pathology in the United States, when the US Food and Drug Administration announced its approval of the Philips IntelliSitePathology Solution for primary diagnosis in surgical pathology.”

• Subsequently:– Aperio AT2 DX system approved, May 2019

Whole-slide imaging validation studies for primary diagnosis

(Pantanowitz L, et al. J. Pathol Inform 2018; 9: 40)

Deep learning algorithm for improving Gleason scoring

(Nagpal K, et al. MPG DigitalMed.2019; 2: 48)

• Main author works at Google AI Healthcare• Gleason scoring whole-slide images of prostatectomies• Training set: 1226 slides• Independent validation set: 331 slides• “Expert” urologic pathologist acted as standard• Results (mean accuracy of grade grouping in validation set):

– 29 general pathologists: 0.61– Deep learning (machine): 0.70

• Conclusion: Machine vision as accurate (or better) than general pathologists

Artificial intelligence for diagnosis and grading of prostate cancer in biopsies: a population-based, diagnostic study

(Strom P, et al. Lancet Oncol 2020 (Jan 8 publication on line))

• Goal: Develop an artificial intelligence (AI) system with clinically acceptable accuracy for prostate cancer detection, localisation, and Gleason grading from digitized images

• Methods: – Training set: 6682 needle core biopsies were used to train deep neural networks– Validation set 1: Independent set of 1631 biopsies from 246 men– Validation set 2: Independent set of 330 biopsies from 73 men– Validation set 3: 87 biopsies individually graded by 23 experienced urological

pathologists• Results:• Benign vs malignant: ROC = 0.99 for both Validation sets 1 and 2• Correlation for cancer length (0.96 and 0.87 for Validation sets 1 and 2)• Gleason grading by AI: mean pairwise kappa of 0·62, similar to the experts (0·60–0·73)• Conclusion: An AI system can be trained to detect and grade cancer in prostate needle biopsy

samples at a ranking comparable to that of international experts in prostate pathology.

Artifical Intelligence (AI) Algorithms for Digital

Pathology Cleared by FDA (through July 2019)

Current Applications Description

Replacement of Glass Slide Pathology

For primary diagnosis

Telepathology For primary diagnosis and second opinion consultations

Teaching, quality control, and proficiency testing

Shared images obviate the need for glass slide transfer

Protein/Chemical determination

Allows documentation of the location and relative amount of select proteins and chemicals

Morphologic and quantitative computer-assisted analysis

Standardization of analysis of cell, tissue and organ samples; Rapid, inexpensive, and accurate study of microscopic findings; avoids human interaction and error

Use of Digital Pathology Among Attendees of the 4th Nordic Symposium on Digital Pathology, 2016

Barriers to Implementation of Digital Pathology (DP)

• Standardization of imaging • Better, faster, and cheaper• Cost-effective• Rules and regulations need to facilitate DP• Algorithms need to better mimic real pathology

practice• Pathologists need to be convinced

Slide Disposal: Current vs. DP

Ship to Waste Store 10 Years

Current

Digital Pathology

Whole Slide Imaging Requirements

• High-throughput automated Digital Pathology system (hardware, software, and LIS integration)

• Large and expandable memory storage and backup owing to the “big data” demands of digitization

• Sufficient internet pipeline for data transfer• Delivery system of images to pathologist (probably

with archiving included)• IT team to support the service

Innovations in Urologic Pathology: 2020

•Digital Pathology•3D Reconstruction•Immunotherapy

Confocal Microscopy: the Future?

New Optical Method “Cuts” and Examines Prostate Cancer Biopsies During Surgery

SelectScience June 28, 2017

Dr J. Quincy Brown, Assistant Professor of Biomedical Engineering, Tulane Univ

Large-scale 3-dimensional quantitative imaging of tissues: state-of-the-art and translational implications

Recent developments in automated optical sectioningmicroscope systems have enabled… high resolution 3D microscopy at the scale of millimeters in… tissues. This powerful technology allows… an unprecedented level of detail, while preserving the spatial context… Such technology will also enable researchers to explore cellular and molecular signatures within tissue and correlate with disease course. This will… facilitate a precision medicine approach to assess the response to treatment.

(Winfree S, et al. Transl Med July 22, 2017)

Light-Scatter Microscopy for Optical Laser Slicing of Tissue an 3D Recontruction

Reder N, et al. Arch Pathol Lab Med 2019; 143:1069

Optical Slicing by Laser

Prostate Needle Biopsy

Regular H & ELight Scatter

Innovations in Urologic Pathology: 2020

•Digital Pathology•3D Reconstruction•Prostate Cancer Immunotherapy

Overall Survival in Men with Metastatic Castrate-Resistant Prostate Cancer

Parker, C., et al. (2013). Alpha emitter radium-223 and survival in metastatic prostate cancer. N.Engl. J. Med, 369(3), 213–223

Prostate Cancer Immunotherapy

• Current Status: Disappointing• New Approach: Multiplex Combination Immunotherapy

PAP-stimulated dendritic cells (Provenge; Sipuleucel-T): Modest benefit

(Kantoff PW, et al. N Engl J Med 2010; 363:411)

• Only immunotherapy approved for prostate cancer

– No PSA change

– No tumor regression

– No increase progression free survival

– Increased overall survival: 4 months

– $105,000 (U.S.) per treatment

Ipilimumab (anti-CTLA4) vs Placebo after Radiotherapy in

Metastatic Prostate Cancer(Kwon E, et al. Lancet Oncol

2014)

No difference in OS 1% death rate: Ipilimumab

Randomized, Double-Blind, Phase III Trial of Ipilimumab (anti-CTLA-4) Versus Placebo in Asymptomatic or Minimally Symptomatic Patients With

Metastatic Chemotherapy-Naive Castration-Resistant

Prostate Cancer(Beer TM, et al. Lancet Oncol 2017)

No difference in OS 2% death rate: Ipilimumab

PROSTVAC (Poxviral-based PSA-targeted vaccine):No benefit

(Parsons, JK et al. Eur Urol Focus, Sept., 2018)

• PROSPECT trial: Randomized phase 3 trial in mCRPC

• Two recombinant pox-virus vectors: vaccinia as the primary immunotherapy, followed by boosters employing fowlpox, to provoke immune responses against PSA. Both vectors contain three T-cell costimulatory molecules (TRICOM).

• Combined with GM-CSF

• 1,297 patients at more than 200 sites in 15 countries

• Trial stopped owing to futility

Immunotherapy for prostate cancer: Is prostate cancer an immune-responsive tumor?

(Slovin SF. Curr Opin Urol 2016)• “Prostate cancer… an immunologic conundrum.”• “Checkpoint inhibitors (PD-1 inhibitors)…have little or no activity.”

Immunotherapy for prostate cancer: Immuno-cold or the tip of the iceberg?

(Lancetti AL et al. . Curr Opin Urol 2017)

”…negative late phase trials for ipilimumab monotherapy and discouraging early phase results for [PD-1] 1 blockade.”

Ipilimumab (anti-CTLA4) plus nivolumab (PD-1 inhibitor) and DNA-repair defects in AR-V7-expressing metastatic prostate cancer

(Boudadi K, et al. Oncotarget, June, 2018)

• “Overall… [no] clinical activity…primary endpoint was not met.”• “Encouraging activity…in subset [with]...DNA-repair genes.”

Prostate Cancer Immunotherapy

• Current Status: Disappointing• New Approach: Multiplex Combination Immunotherapy

Multiplex is the use of different methods for modulating the immune system at the same time:

Ablation Therapy Immunotherapy Drugs Chemotherapy Drug (low-

dose)

Solution to Unmet Need: Multiplex Combination Immunotherapy

Low-Dose Chemotherapy

Drug

Immunotherapy Drugs

Chemotherapy Drug

• Use the patient’s own immune system to destroy cancer (personal vaccine)

• Ablation (proprietary method): Destroy cancer cells and release all cancer-associated

proteins (antigens)• Combination Low-Dose Immunotherapy: Use checkpoint inhibitor drugs to stimulate killer T-

cells and block Tregs• Low-Dose chemotherapy: Block Tregs

Potential Solution to Unmet Need: Multiplex Combination Immunotherapy

4 Mechanisms of Action

Solution to Unmet Need: Multiplex Combination Immunotherapy

ExposeAll Cancer Proteins

UnmaskCancer

Release Brakes on Immune System

SuperchargeKiller T-cells

Ablation kills cancer cells, releasing cancer-specific proteins (antigens).

Immunotherapy unmasks (de-cloaks) individual cancer cells

Immunotherapy and low-dose chemotherapy block the “off” switch

Immunotherapy stimulates the immune system to kill cancer cells

Goal: Harness the Abscopal Effect

Treat cancer here

Abscopal response here

Latin ab (position away from) and scopus (target)Also referred to as “bystander” effect

Patient #1: Metastatic Castrate-Resistant Prostate Cancer• 72 year-old diagnosed with Gleason 8• Treatment: Surgery, radiation, Lupron, Casodex• Recurrence: Treated with Zytiga and 13 rounds of che

motherapy (taxotere and carbazetaxel)-- failed• 2015: Bladder and rectal invasion, nodal metastases,

obstruction of both ureters and urethra, supra-pubic • tube• Recommendation: Hospice care• Treatment: Multiplex Combination Immunotherapy

PSA

Months

Patient #1: Complete Response of PSA

Treatment: Multiplex Combination Immunotherapy

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Patient #1: Complete Response of Distant Metastases

(Abscopal Effect)

Before After

Patient #1: Post-Therapy Biopsies: No cancer

Stents removed and Suprapubic tube removed

Alive and cancer-free at 4 yr. 7 months ( as of Nov, 2019)PSA remains at < 0.01 ng/mL

Patient #2: Hormone-Naïve Prostate Cancerwith Lymph Node Metastases

• 68 year-old, asymptomatic, PSA 130 ng/mL• Gleason 8 with extra-prostatic extension of cancer on MRI• 2 cm lymph node metastases, right iliac chain

Copyright 2017-RFEMB Holdings LLCTUMOR TUMOR GONE

Before After

Treatment

PSA Treatment

Normal Urinary FunctionNormal Sexual Function

Patient #2: Complete Response

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Treatments: Multiplex Combination Immunotherapy

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Region 1129648.91.81.71.82

Before After

Patient #2: Complete Response

Alive and Cancer-free for 3 yr. 5 monthsPSA= 1.7 ng/mL (prostate intact)

Patient #3: Unresectable mass growing into pelvic sidewall and rectum

• 59 yr old• PSA 54 ng/mL•Unresectable mass growing into the

pelvic sidewall and rectum

PSA

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TREATMENT #1

Patient #3: Unresectable mass in pelvic sidewall

TREATMENT #2

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Treatments: Non-thermal ablation +Immunotherapeutics, includingPD-1 inhibitor and Anti-CTLA-4

Patient 3: Rectal and pelvic wall involvement resolved; prostate normal

Before After

• 17 patients with metastatic prostate cancer

Multiplex Combination ImmunotherapyAnecdotal Results: 2015-2018

Clinical Result # Pts. (%)

Complete response (CR) 6/17 (35%)

CR progressed 1/6 (17%)

Radiographic response 7/17 (41%)

PSA decline 12/15 (75%)

PSA decline > 50% 9/16 (56%)

Deceased 1/17 (6%)

Adverse Events # Pts. (%)

Serious (Grade 3 or 4)(Syndrome of Inappropriate ADH; Infectious prostatitis; Perinephric abscess)

3/17 (18%)

Low Grade (Grade 1 or 2)(Hypothyroidism, 4 pts.; Skin rash, 4; Nausea & vomiting, 1;

9/17 (53%)

Onik G, Bostwick DG, et al. Abscopal Effect of in situ Tumor Lysis Coupled with Local Immunotherapy: Complete Regression of Prostate Cancer Metastases. Submitted (Oct 2019)

Additional Results (all with metastatic cancer)

Pancreatic cancer: 2 patients treated; metastases gone within 3 months; one is alive and cancer free at 2.3 years; the other is cancer-free at 14 monthsColon cancer: 2 patients treated; one had massive anorectal tumor (11 cm) that shrank in half after one treatment– pt. still alive 2 years later. Another patient’s tumor shrank sufficiently to reopen the colonic channel without need for colostomy-- alive 1 year later.Lung cancer: 2 patients treated. One had tumor regression, but died of pneumonia at 6 weeks. The other had moderate shrinkage of scattered metastases; still alive at 2 years.

Study Limitations• Observational results; not controlled

clinical trial• Small number of patients• No long-term follow-up beyond 4.7 yr.• Off-label use of drugs and devices• Two-provider experience

Phase II trial (Abscopal 1001)Design

• 32 patients with metastatic prostate cancer• 3 sites (U.S.)• FDA-cleared trial design• Began in July 2019• Primary endpoint: PSA drop of 50%• Secondary endpoint: Radiographic response at

6 months using iRECIST criteria

Phase Ib/IIa trial (Abscopal 3001)Design

• 32 patients with metastatic solid carcinoma (bladder, kidney, pancreas, ovary, skin, etc.)

• 5 sites in U.S.; 1 likely in China (pending)• FDA-cleared trial design (Oct. 2019)• Begins in early 2020• Primary endpoint: Radiographic response at 6

months using iRECIST criteria

Phase II trial (Abscopal 1001)Results (as of Dec 4, 2019)

• 9 patients treated• Primary endpoint (PSA drops by half): 3 of 9 (33%)• Secondary endpoint (radiographic changes): Pending• Adverse events:

– Pneumonia, probably unrelated (1 [11%])– Nausea, probably unlreated (1 [11%])

ConclusionMultiplex Combination Immunotherapy may be useful in treatment of

prostate cancer and other cancers

The Optimistic Urologic Pathologist: Select innovations in diagnosis,

prognosis, and treatmentDavid G. Bostwick, MD, MB

Overall Survival in Men with High-Volume Metastatic Prostate Cancer

• Sweeney C, et al. Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer (mPRCa): An ECOG-led phase III randomized trial. J Clin Oncol. 2014;32(suppl)..

ADT: Androgen Deprivation TherapyD: Docetaxol

Commercial Applications

Description Commercial Potential

Needs Prior to Commercial Use

Potential Competitors

Slide waste disposal service

B2B service for laboratories to dispose of glass slides (hazardous waste) after digitization

High immediate unmet need that will grow quickly

Autoclave and slide pulverizer; quality assurance program to avoid destruction of slides prior to archiving

Uncertain; no current competitors, so first-mover advantage possible

Digital Pathology Service

Management

B2B service for laboratories to fulfill technical, training, governance and regulatory issues

High; immediate need Create support program; branding and marketing

None yet; expect competitors now that FDA approval has been granted; likely from DP industry

Slide digitization service

B2B service for laboratories to digitize slide images prior to archiving

High immediate need that will grow quickly; expect price erosion

Software and hardware integration; should be combined with archiving

All DP industry vendors

Cloud-based archiving service

B2B service for laboratories to archive slide images

High immediate need that will grow quickly; expect price erosion

Software, hardware, and web site; branding and marketing

All cloud-based providers; all DP industry vendors

Algorithm As a Service or Product

B2B service or product for automated diagnosis–disruptive technology

High immediate need; expect rapid growth

Validation; FDAclearance required

Academia; entire industry

Slide Number 1Innovations in Urologic Pathology: 2020Slide Number 3Slide Number 4US Food and Drug Administration Approval of Whole Slide Imaging for Primary Diagnosis�Evans A, et al. Arch Pathol Lab Med 2018; 142:1383Whole-slide imaging validation studies for primary diagnosisDeep learning algorithm for improving Gleason scoring�(Nagpal K, et al. MPG DigitalMed.2019; 2: 48)Artificial intelligence for diagnosis and grading of prostate cancer in biopsies: a population-based, diagnostic study�(Strom P, et al. Lancet Oncol 2020 (Jan 8 publication on line))Artifical Intelligence (AI) Algorithms for Digital Pathology Cleared by FDA (through July 2019)Slide Number 10Use of Digital Pathology Among Attendees of the 4th Nordic Symposium on Digital Pathology, 2016Barriers to Implementation of Digital Pathology (DP)Slide Disposal: Current vs. DPWhole Slide Imaging RequirementsInnovations in Urologic Pathology: 2020Confocal Microscopy: the Future?New Optical Method “Cuts” and Examines Prostate Cancer Biopsies During SurgeryLarge-scale 3-dimensional quantitative imaging of tissues: state-of-the-art and translational implicationsLight-Scatter Microscopy for Optical Laser Slicing of Tissue an 3D Recontruction�Reder N, et al. Arch Pathol Lab Med 2019; 143:1069Innovations in Urologic Pathology: 2020Overall Survival in Men with Metastatic Castrate-Resistant Prostate CancerProstate Cancer ImmunotherapyPAP-stimulated dendritic cells �(Provenge; Sipuleucel-T): Modest benefit�(Kantoff PW, et al. N Engl J Med 2010; 363:411) Slide Number 24Ipilimumab (anti-CTLA4) vs Placebo after Radiotherapy in Metastatic Prostate Cancer�(Kwon E, et al. Lancet Oncol 2014)PROSTVAC (Poxviral-based PSA-targeted vaccine):�No benefit�(Parsons, JK et al. Eur Urol Focus, Sept., 2018)Immunotherapy for prostate cancer: �Is prostate cancer an immune-responsive tumor?�(Slovin SF. Curr Opin Urol 2016)Prostate Cancer ImmunotherapySlide Number 29Slide Number 30Slide Number 31Slide Number 32Patient #1: �Metastatic Castrate-Resistant Prostate CancerSlide Number 34Patient #1: �Complete Response of Distant Metastases �(Abscopal Effect)Patient #1: Post-Therapy Biopsies: �No cancerPatient #2: Hormone-Naïve Prostate Cancer� with Lymph Node MetastasesSlide Number 38Slide Number 39Patient #3: Unresectable mass growing into pelvic sidewall and rectumPatient #3: Unresectable mass in pelvic sidewallPatient 3: Rectal and pelvic wall involvement resolved; prostate normalSlide Number 43Additional Results �(all with metastatic cancer)Study LimitationsPhase II trial (Abscopal 1001)�DesignPhase Ib/IIa trial (Abscopal 3001)�DesignPhase II trial (Abscopal 1001)�Results (as of Dec 4, 2019)ConclusionSlide Number 50Slide Number 51Overall Survival in Men with High-Volume Metastatic Prostate CancerSlide Number 53