City of Hope

Preeminent health care innovator and leader Glenn D. Steele Jr, MD, PhD, has been elected the new board chair of City of Hope, the world-renowned cancer and diabetes research and treatment center, effective June 1. He joined the City of Hope Board of Directors in January 2016. Prior to becoming chair, he was chair of the Executive Compensation and Governance Committee from 2018-2020.

“City of Hope has benefited from Glenn’s vision, expertise and leadership on our board for a number of years,” said City of Hope President and CEO Robert Stone. “His background and accomplishments as an academic physician-scientist have played an important role in propelling our research and innovative patient care. He will carry on the exceptional work of our immediate past chair, Selwyn Isakow, founder and chief executive officer of The Oxford Investment Group, to lead City of Hope into the future.”

“City of Hope is an extraordinary organization at the center of eliminating cancer and diabetes,” said Steele, “and I am honored to be elected as board chair.” Steele serves as chairman of GSteele Health Solutions, an independently-operated venture launched to help health care organizations create value and improve quality. He is the former chairman of xG Health Solutions and former president and chief executive officer of Geisinger Health System, an integrated health services organization recognized for its innovative use of the electronic health record and the development and implementation of leading-edge care models.

Steele’s leadership background is extensive. He is past chairman of the American Board of Surgery, and serves on numerous for-profit and not-for-profit boards and national committees, including vice chair of Health Transformation Alliance — founded by over 50 of America’s most successful corporations with a common goal to improve health care outcomes for their 6.5-7 million sponsored lives, Bucknell University Board of Trustees as an emeritus trustee, Stanford Board of Fellows, Peterson Center on Healthcare Advisory Board, and serves as an adviser on the private equity firms of General Atlantic and LRVHealth.

A member of the National Academy of Medicine, his extensive experience also includes academic leadership positions. Prior to leading Geisinger, Steele served as the dean of the Biological Sciences Division and the Pritzker School of Medicine and vice president for medical affairs at University of Chicago, as well as the Richard T. Crane Professor in the Department of Surgery. Prior to that, he was the William V. McDermott Professor of Surgery at Harvard Medical School. His investigations have focused on the cell biology of gastrointestinal cancer and pre-cancer and, most recently, on innovations in health care delivery and financing. A prolific writer, he is the author or co-author of more than 500 scientific and professional articles.

Steele is the recipient of numerous awards, including New York University’s School of Medicine’s Solomon A. Berson Medical Alumni Achievement Award in Health Science, Medicine and the Arts, the American Hospital Association's Justin Ford Kimball Innovators Award and National Center for Healthcare Leadership’s Gail L. Warden Healthcare Leadership Award. He has been named numerous times to Modern Healthcare’s “50 Most Powerful Physician Executives in Healthcare” and Becker’s Hospital Review “100 Non-Profit Hospital, Health System CEOs to Know” list.

Steele received his bachelor’s degree in history and literature from Harvard College and his medical degree from New York University School of Medicine. He completed his internship and residency in surgery at University of Colorado, where he was also a fellow of the American Cancer Society. He earned his doctorate in microbiology at Lund University in Sweden.

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 Preeminent health care innovator and leader Glenn D. Steele Jr, MD, PhD, has been elected the new board chair of City of Hope effective June 1. 

Glenn D. Steele Jr, MD, PhD, Renowned Health Care Leader and Innovator, Named Chair of City of Hope Board of Directors

The combination of cabozantinib (Cabometyx) and atezolizumab (Tecentriq) has shown promising response rates across several tumors types, but now it has also shown encouraging clinical activity in heavily pretreated patients with urothelial carcinoma, according to Sumanta K. Pal, MD.

In the multicenter, phase 1b COSMIC-021 (NCT03170960) trial, investigators evaluated the combination of cabozantinib with atezolizumab in various solid tumors. Results from the urothelial carcinoma expansion cohort 2 (n = 30) were presented at the 

. At a median follow-up of 19.7 months, the objective response rate with the combination was 27%, with 2 (6.7%) complete responses and 6 (20%) partial responses. The disease control rate was 63% and 16 (53%) patients experienced a reduction in target lesion size.

Additionally, the median duration of response was not reached with the longest response ongoing at more than 15.6 months. The median time to response was 3.0 months. The median progression-free survival (PFS) was 5.4 months (95% CI, 1.5-7.6) with 22 PFS events observed.

“There’s a real reason to keep an eye on the data emerging from COSMIC-021,” said Pal. “Like a fine wine, the study just keeps getting better and better with more and more interesting data pouring out of it.”

, Pal, a clinical professor in the Department of Medical Oncology & Therapeutics Research and codirector of the Kidney Cancer Program at City of Hope, discussed the clinical implications of the COSMIC-021 trial and highlighted other exciting research efforts being made in genitourinary cancers.

: Could you provide some background to the 

: COSMIC-021 is a very interesting study. It actually began as a trial that was intended to just enlist patients with genitourinary cancers. We began with 3 cohorts in bladder cancer, kidney cancer, and prostate cancer. Then, gradually, over the course of time, it actually fanned out into this massive entity, and now it focuses on over 20 cohorts of patients, ranging from liver cancer to breast cancer, and so on. At this year's ASCO meeting, we were very excited to unleash some of our data in prostate cancer, bladder cancer, and lung cancer.

What is it about the combination of cabozantinib and atezolizumab that has led to this synergy?

Whenever we talk about a drug like cabozantinib, we first and foremost discuss its properties that [allow it to] inhibit VEGF, but the agent does much more than that. Cabozantinib is a MET inhibitor, an AXL inhibitor, and beyond that, we think that it has complex effects on the immune milieu. [The agent] seems to shift the direction of myeloid-derived suppressor cells away from tumors, and it has several other [components] that we believe augment the impact of immunotherapy. There's real reason to believe that there's true synergy between cabozantinib and immunotherapy.

Could you discuss the urothelial cancer cohort that this combination was evaluated in? What did the patient population look like and what was the clinical activity observed with this approach?

In this particular cohort, we looked at patients who had received prior platinum-based chemotherapy; there were a total of 30 patients in this cohort. One of the main things I would emphasize is that this was a very heavily pretreated cohort. When you look at our data, you'll see in the abstract that amongst these 30 patients, we had a healthy number, 47%, who had received greater than or equal to 2 prior lines of therapy. When you contrast this against some of the other data that's coming out for combinations of immunotherapy and targeted therapy bear that number in mind: 47% really had very, very extensive prior treatment.

Where do you see this combination fitting best in the urothelial cancer treatment paradigm? Do you foresee it being used in the frontline? What does the future hold?

At ASCO this year, we all project that we're going to see some of the maintenance data for immunotherapy in bladder cancer. The earlier we can sequence these combinations of treatment, the better. I can easily envision cabozantinib and atezolizumab really supplanting chemotherapy in the frontline setting. In fact, we have a cohort in COSMIC-021 that's exploring just that premise. However, there are other settings even ahead of that, that I would be inspired to examine. For instance, at the Genitourinary Cancers Symposium [earlier this year], we saw some data for combinations of TKI and immunotherapy in the neoadjuvant setting. I'd love to see that.

It hasn't been lost on me that we haven't done a deep dive into the results from this trial. What we saw in this study was a 27% response rate, and that response rate stands favorably to anything that I've seen in the second-, third-line setting, and beyond in bladder cancer. There's some real reason to believe that if we slide this regimen up front it is going to be even more active.

Are any biomarker research efforts being made with COSMIC-021?

Absolutely. We have a very robust portfolio of relative studies that are accompanying this trial. Particularly, I'm excited about [the work being done] in T-cell populations, where we’re looking at fluxes and effector T cells and cytotoxic T cells as patients go through therapy. Those [efforts] are going to shed light and maybe even offer some perspective on the true contribution of cabozantinib within the study population.

Is there anything that you would like to add regarding this trial?

I will give a quick shout out to COSMIC-021 in the prostate cancer setting because there we're seeing some really remarkable response data, once again. [Those data have] propagated a phase 3 clinical trial that is going to compare cabozantinib plus atezolizumab with standard therapy.

What other studies presented at this year’s ASCO virtual meeting are you most excited about?

I might give some focus to a study that we did in collaboration with my colleagues at The Translational Genomics Research Institute. This abstract is being led by my colleague, Nick Salgia, a brilliant student who is going to be starting medical school next year. He synthesized a lot of nice data pertaining to genomics and kidney cancer. We have a very heavily annotated cohort of patients who received whole-exome sequencing and RNA-sequencing (RNA-seq). [We knew] that TBR1 seemed to bear some association with clinical outcome with immunotherapy, but he also identified and confirmed in RNA-seq data that TERT promoters seems to be a predictor of immunotherapy resistance. I'm very excited about that work.

Is there anything else that you would like to highlight? How has your practice been doing in relation to COVID-19?

COVID-19 has put a damper on so many elements of clinical practice, but a necessary damper. I'm excited to see some operations in our hospital resuming like elective surgeries and so forth. It really is important for us to continue to maintain a conscious stance. For instance, we're really trying our best to prevent overcrowding within our waiting rooms and trying to ensure that patients aren't coming to visits they could otherwise have via telephone or via telemedicine. Those measures are going to really help us as we try to bridge this pandemic.

Pal SK, Agarwal N, Loriot Y, et al. Cabozantinib in combination with atezolizumab in urothelial carcinoma previously treated with platinum-containing chemotherapy: Results from cohort 2 of the COSMIC-021 study. 

. 2020;38(suppl 15):5013. doi:10.1200/JCO.2020.38.15_suppl.5013

Sumanta K. Pal, MD, discusses the clinical implications of the COSMIC-021 trial and highlights other exciting research efforts being made in genitourinary cancers.

Pal Previews Promise of Cabozantinib Plus Atezolizumab in Heavily Pretreated Urothelial Cancer

The combination of cabozantinib (Cabometyx) and atezolizumab (Tecentriq) has shown promising response rates across several tumors types, but now it has also shown encouraging clinical activity in heavily pretreated patients with urothelial carcinoma, according to Sumanta K. Pal, MD.

In the multicenter, phase 1b COSMIC-021 (NCT03170960) trial, investigators evaluated the combination of cabozantinib with atezolizumab in various solid tumors. Results from the urothelial carcinoma expansion cohort 2 (n = 30) were presented at the 

.

At a median follow-up of 19.7 months, the objective response rate with the combination was 27%, with 2 (6.7%) complete responses and 6 (20%) partial responses. The disease control rate was 63% and 16 (53%) patients experienced a reduction in target lesion size.

, Pal, a clinical professor in the Department of Medical Oncology & Therapeutics Research and codirector of the Kidney Cancer Program at City of Hope, discussed the clinical implications of this study and other exciting abstracts presented at the 2020 ASCO Virtual Scientific Presentation.

: Could you provide some background to the

COVID-19 has put a damper on so many elements of clinical practice, but a necessary damper. I'm excited to see some operations in our hospital resuming like elective surgeries and so forth. It really is important for us to continue to maintain a conscious stance. For instance, we're really trying our best to prevent overcrowding within our waiting rooms and trying to ensure that patients aren't coming to visits they could otherwise have via telephone or via telemedicine. Those measures are going to really help us as we try to bridge this pandemic. 

Vincent Chung, MD, associate clinical professor, Department of Medical Oncology and Therapeutics Research, director of the Phase I Program, City of Hope, discusses findings from a pilot study (NCT02336087) evaluating the safety of adding dietary supplements to chemotherapy in patients with unresectable pancreatic cancer.

The study enrolled 21 patients to receive 17 supplements in the form of 12 pills and 2 smoothie packets with metformin and gemcitabine plus nab-paclitaxel (Abraxane).

The overall survival and progression-free survival were 8.9 months and 5.4 months respectively. A partial response rate of 29% was observed with the chemotherapy/supplement combination. These results were comparable to findings from the randomized phase III MPACT trial, says Chung.

Investigators also evaluated the safety of this regimen as many patients with pancreatic cancer experience gastrointestinal toxicities with treatment, explains Chung. Findings revealed that the treatment was generally well tolerated; only 2 patients came off study early.

Some patients who received the supplement/chemotherapy combination reported higher energy levels and a general improvement in well-being, explains Chung. As such, further investigation is needed to determine if supplements can improve patients

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Vincent Chung, MD, discusses findings from a pilot study evaluating the safety of adding dietary supplements to chemotherapy in patients with unresectable pancreatic cancer.

Dr. Chung on Adding Dietary Supplements to Chemotherapy in Pancreatic Cancer

David S. Snyder, MD, associate chair of the Department of Hematology and Hematopoietic Cell Transplantation, professor of Hematology and Hematopoietic Cell Transplantation, and hematologist/oncologist at City of Hope, discusses how ruxolitinib (Jakafi) and fedratinib (Inrebic) may be used to pave the way toward transplant for patients with myelofibrosis.

The drugs that are available for the treatment of MPNs, ruxolitinib and fedratinib, are effective at helping to control systemic symptoms and to help reduce splenomegaly, says Snyder. However, they do not cure the disease nor do they change the natural history of the diseases. As such, ruxolitinib and fedratinib are not substitutes for transplant but they may help pave the way toward transplant. Patients who are treated with those drugs may experience a reduction in the size of their spleen and improvement in performance status, which are characteristics that could help their outcomes after transplant, concludes Snyder.

David S. Snyder, MD, discusses how ruxolitinib and fedratinib may be used to pave the way toward transplant for patients with myelofibrosis.

Dr. Snyder on How Ruxolitinib and Fedratinib May Pave the Way to Transplant in Myelofibrosis

Vincent Chung, MD, associate clinical professor, Department of Medical Oncology and Therapeutics Research, director of the Phase I Program, City of Hope, discusses the importance of genomic testing in pancreatic cancer.

While actionable mutations are rare in patients with advanced disease, there are targeted agents that are approved for use in the space, explains Chung. For example, larotrectinib (Vitrakvi) was approved in November 2018 for the treatment of patients with solid tumors who harbor an 

Additionally, immunotherapy should be considered for the 1% to 2% of patients with pancreatic cancer who have microsatellite instability—high disease, says Chung.

The National Comprehensive Cancer Network guidelines recommend that patients with advanced pancreatic cancer undergo genomic testing. Moreover, all patients with pancreatic cancer should receive germline testing, concludes Chung.

Vincent Chung, MD, discusses the importance of genomic testing in pancreatic cancer.



Dr. Chung on the Importance of Genomic Testing in Pancreatic Cancer

David S. Snyder, MD, associate chair of the Department of Hematology and Hematopoietic Cell Transplantation, professor of Hematology and Hematopoietic Cell Transplantation, and hematologist/oncologist at City of Hope, discusses tools to improve the use of allogeneic stem cell transplant in myelofibrosis.

Allogeneic stem cell transplant is currently the only curative option available to patients with myelofibrosis, says Snyder. Investigators are working on developing better tools to select the appropriate candidates for transplant, improve outcomes after the procedure, and predict who is likely to do well post-transplant, says Snyder.

To this end, new prognostic scoring systems are under development. The original systems used in this space was the Dynamic International Prognostic Scoring System (DIPSS) and DIPSS Plus. Other systems have since emerged, such as the latest the Mutation-Enhanced International Prognostic Score System (MIPSS) and MIPSS70-plus version 2.0.

These systems incorporate molecular and karyotypic information and help stratify patients in terms of prognosis and survival, not necessarily after transplant but overall with general treatment, according to Snyder. While these tools may help decide which patients should be considered for transplant, they do not help predict what outcomes will look like after transplant, concludes Snyder.

David S. Snyder, MD, discusses tools to improve the use of allogeneic stem cell transplant in myelofibrosis.

Dr. Snyder on Tools to Improve Use of Allogeneic Stem Cell Transplant in Myelofibrosis

Joseph Chao, MD, assistant clinical professor, Department of Medical Oncology and Therapeutics Research, City of Hope, discusses the utility of microsatellite instability (MSI) status as a prognostic biomarker in gastric and gastroesophageal junction (GEJ) cancer.

Typically, patients with stage IV gastric/GEJ cancer have a relatively poor prognosis, says Chao. However, MSI—high (MSI-H) patients have improved outcomes with PD-1 inhibitors.

In September 2017, the FDA approved the PD-1 inhibitor pembrolizumab (Keytruda) for the treatment patients with PD-L1—positive recurrent or advanced gastric/GEJ adenocarcinoma who have received ≥2 prior lines of therapy.

A comparative analysis of the phase II KEYNOTE-059 and phase III KEYNOTE-061 and KEYNOTE-062 trials indicated that pembrolizumab monotherapy elicited clinically meaningful efficacy and more durable responses compared with chemotherapy in patients with a combined positive score ≥10 in the first-, second-, and third-line settings.

In Japan, regulatory authorities approved nivolumab (Opdivo) for patients with gastric/GEJ cancer regardless of biomarker status. However, MSI-H patients who receive nivolumab derive favorable outcomes compared with patients with microsatellite stable disease, concludes Chao.

Joseph Chao, MD, discusses the utility of microsatellite instability (MSI) status as a prognostic biomarker in gastric and gastroesophageal cancer.

Dr. Chao on the Utility of MSI as a Biomarker in Gastric/GEJ Cancer

City of Hope scientists have developed and tested the first chimeric antigen receptor (CAR) T-cell therapy using chlorotoxin (CLTX), a component of scorpion venom, to direct T cells to target brain tumor cells, according to a preclinical study published today in Science Translational Medicine. The institution has also opened the first in-human clinical trial to use the therapy.

CARs commonly incorporate a monoclonal antibody sequence in their targeting domain, enabling CAR T cells to recognize antigens and kill tumor cells. In contrast, the CLTX-CAR uses a 36-amino acid peptide sequence first isolated from death stalker scorpion venom and now engineered to serve as the CAR recognition domain.

Glioblastoma (GBM), the most common type of brain tumor, is also among the most deadly of human cancers, according to the American Cancer Society. It is particularly difficult to treat because the tumors are disseminated throughout the brain. Efforts to develop immunotherapies, including CAR T cells, for GBM must also contend with a high degree of heterogeneity within these tumors.

For the study, City of Hope researchers used tumor cells in resection samples from a cohort of patients with GBM to compare CLTX binding with expression of antigens currently under investigation as CAR T cell targets, including IL13Rα2, HER2 and EGFR. They found that CLTX bound to a greater proportion of patient tumors, and cells within these tumors.

CLTX binding included the GBM stem-like cells thought to seed tumor recurrence. Consistent with these observations, CLTX-CAR T cells recognized and killed broad populations of GBM cells while ignoring nontumor cells in the brain and other organs. The study team demonstrated that CLTX-directed CAR T cells are highly effective at selectively killing human GBM cells in cell-based assays and in animal models without off-tumor targeting and toxicity.

“Our chlorotoxin-incorporating CAR expands the populations of solid tumors potentially targeted by CAR T cell therapy, which is particularly needed for patients with cancers that are difficult to treat such as glioblastoma,” said Christine Brown, Ph.D., City of Hope’s Heritage Provider Network Professor in Immunotherapy and deputy director of T Cell Therapeutics Research Laboratory. “This is a completely new targeting strategy for CAR T therapy with CARs incorporating a recognition structure different from other CARs.”

Michael Barish, Ph.D., City of Hope professor and chair of the Department of Developmental and Stem Cell Biology, initiated the development of a CAR using chlorotoxin to target GBM cells. The peptide has been used as an imaging agent to guide GBM resection surgery, and to carry radioisotopes and other therapeutics to GBM tumors.

“Much like a scorpion uses toxin components of its venom to target and kill its prey, we’re using chlorotoxin to direct the T cells to target the tumor cells with the added advantage that the CLTX-CAR T cells are mobile and actively surveilling the brain looking for appropriate targets,” Barish said. “We are not actually injecting a toxin, but exploiting CLTX’s binding properties in the design of the CAR. The idea was to develop a CAR that would target T cells to a wider variety of GBM tumor cells than the other antibody-based CARs.”

“The notion is that the higher the proportion of tumor cells that one can kill at the beginning of treatment, the greater the probability of slowing down or stopping GBM growth and recurrence,” Barish added.

Dongrui Wang, a doctoral candidate in City of Hope’s Irell & Manella Graduate School of Biological Sciences, was the lead scientist to establish and optimize the CLTX-CAR T cell platform and to determine that cell surface protein matrix metalloprotease 2 is required for CLTX-CAR T cell activation. He added that “while people might think the chlorotoxin is what kills the GBM cells, what actually eradicates them is the tumor-specific binding and activation of the CAR T cells.”

Based on the promising findings of this study, the study team intends to bring this therapy to patients diagnosed with GBM with the hope of improving outcomes against this thus far intractable cancer. With recently granted Food and Drug Administration approval to proceed, the first-in-human clinical trial using the CLTX-CAR T cells is now screening potential patients.

This work was supported by the Ben & Catherine Ivy Foundation of Scottsdale, Arizona, and the clinical trial will be supported by The Marcus Foundation of Atlanta.

City of Hope, a recognized leader in CAR T cell therapies for glioblastoma and other cancers, has treated nearly 500 patients since its CAR T program started in the late 1990s. The institution continues to have one of the most comprehensive CAR T cell clinical research programs in the world — it currently has 29 ongoing CAR T clinical trials, including CAR T trials for HER2-positive breast cancer that has spread to the brain, and PSCA-positive bone metastatic prostate cancer. It was the first and only cancer center to treat GBM patients with CAR T cells targeting IL13Rα2, and the first to administer CAR T cell therapy locally in the brain, either by direct injection at the tumor site, through intraventricular infusion into the cerebrospinal fluid, or both. In late 2019, City of Hope opened a first-in-human clinical trial for patients with recurrent glioblastoma combining IL13Rα2-CAR T cells with checkpoint inhibitors nivolumab, an anti-PD1 antibody, and ipilimumab, blocking the CTLA-4 protein.

City of Hope scientists have developed and tested the first CAR T-cell therapy using chlorotoxin, a component of scorpion venom, to direct T cells to target brain tumor cells.

From Scorpion to Immunotherapy: City of Hope Scientists Repurpose Nature's Toxin for First-Of-Its Kind CAR T Cell Therapy to Treat Brain Tumors

Amir Khan, MD, surgical oncologist, City of Hope, discusses a large retrospective database analysis on colorectal cancer (CRC) and gastric cancer presented at the 2020 Gastrointestinal Cancers Symposium.

The study looked at patients who had a diagnosis of gastric cancer or CRC between the ages of 18 and 90 from 2000 to 2012 within the California Cancer Registry, which is linked to an inpatient database within California, explains Khan. The basic dataset covered younger and older adults in both malignancies.

The study examined close to 120,000 patients in the CRC group and nearly 20,000 patients in the gastric cancer group. A univariate and multivariate analyses were performed to look for differences between the younger and older patients in terms of demographic features, clinical features, and histopathologic characteristics of their tumors, as well as survival outcomes, says Khan.

There was no vague cutoff for early onset cancer in young adults and older adults. Instead, patients were stratified into 4 groups based on age: 18 to 40 years, 41 to 49 years, 50 to 64 years, and 65 to 90 years. The 3 older groups were compared with the youngest group to determine differences, concludes Khan.

Amir Khan, MD, discusses a large retrospective database analysis on colorectal cancer and gastric cancer presented at the 2020 Gastrointestinal Cancers Symposium.

City of Hope

Glenn D. Steele Jr, MD, PhD, Renowned Health Care Leader and Innovator, Named Chair of City of Hope Board of Directors

Pal Previews Promise of Cabozantinib Plus Atezolizumab in Heavily Pretreated Urothelial Cancer

Pal Previews Promise of Cabozantinib Plus Atezolizumab in Heavily Pretreated Urothelial Cancer

Dr. Chung on Adding Dietary Supplements to Chemotherapy in Pancreatic Cancer

Dr. Snyder on How Ruxolitinib and Fedratinib May Pave the Way to Transplant in Myelofibrosis

Dr. Chung on the Importance of Genomic Testing in Pancreatic Cancer

Dr. Snyder on Tools to Improve Use of Allogeneic Stem Cell Transplant in Myelofibrosis

Dr. Chao on the Utility of MSI as a Biomarker in Gastric/GEJ Cancer

From Scorpion to Immunotherapy: City of Hope Scientists Repurpose Nature's Toxin for First-Of-Its Kind CAR T Cell Therapy to Treat Brain Tumors

Dr. Khan on Retrospective Analysis of Demographics in CRC and Gastric Cancer