Systemic Sclerosis: A Rare Disease That Requires Several Specialists

by | Feb 26, 2024 | 2021, all stories 2021

Systemic Sclerosis: A Rare Disease That Requires Several Specialists

Systemic Sclerosis: A Rare Disease That Requires Several Specialists

For unknown reasons, autoimmune diseases attack the body insidiously, often wreaking havoc and causing immense disruption to patients’ lives. There are more than 100 autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, and multiple sclerosis.

Systemic sclerosis is another autoimmune disease, characterized by widespread fibrosis (replacement of normal tissue with scar tissue), vasculopathy (affecting blood vessels), and inflammation. It is a particular clinical interest of Lorinda Chung, MD, MS, professor of immunology and rheumatology and dermatology.

Systemic sclerosis is a very rare disease, less common than lupus or rheumatoid arthritis, but more common than dermatomyositis. There is a female predominance (4–5:1); however, men tend to have a worse prognosis. It typically presents in patients from their 30s to their 60s. African American patients definitely have a poorer prognosis than Caucasians, and Asians with the disease do as poorly as African Americans, as was demonstrated in Chung’s recent publication about racial disparities in systemic sclerosis based on the Kaiser Permanente Northern California database.

How Patients With Systemic Sclerosis Present

Chung describes the different manifestations of systemic sclerosis: “There are two major subtypes of systemic sclerosis: diffuse cutaneous and limited cutaneous. The subtypes are purely based on the extent of skin tightening that the patient presents with. Patients with diffuse cutaneous involvement have widespread skin tightening as well as higher likelihood of early and severe internal organ involvement, including the lungs, heart, and kidneys, as well as the muscles and joints.”

One very common feature of systemic sclerosis is Raynaud’s disease, a rare disease that reduces blood flow to the fingers and toes, causing them to turn white and become numb, which occurs in 90% of patients. Patients with the second subtype of systemic sclerosis, the limited subtype, frequently suffer from Raynaud’s and vascular phenomena like digital ulcers. These patients often live for a while without their internal organs being affected but have a higher likelihood of gastrointestinal (GI) and lung involvement later in their disease. Chung explains that “they can get severe dysmotility of their GI tract and also develop pulmonary hypertension. There are some good treatments for pulmonary hypertension, but we really struggle with treatment of the GI manifestations.”

A Special Clinic

There is a unique multidisciplinary clinic every Monday afternoon in Redwood City that focuses on the dermatologic and immunologic aspects of systemic sclerosis. Professor of dermatology David Fiorentino, MD, PhD, helped found the clinic close to 20 years ago because, as he says, “I saw a huge gap in the care of some patients if different doctors weren’t communicating in real time regarding patient care.”

Having patients seen simultaneously by both a dermatologist and a rheumatologist solved that, and the clinic is so successful, says Fiorentino, that “access is a big problem. We’re always scheduling a minimum of three to four months in advance. That is literally our biggest challenge, and it has been almost since the beginning of the clinic.”

The process that patients follow when they attend this clinic is unusual in several ways. For one thing, says Fiorentino, “we don’t see anyone in the clinic whose medical information has not been personally reviewed by either Dr. Chung or me or both. Patients carry around misdiagnoses of rheumatic diseases quite commonly, and clinic appointments are so precious that we need to make sure the appropriate patients are seen in our clinic.”

When patients arrive, they are assigned to a room where their vital signs are recorded and their medications are reconciled. They also change into a gown, which is unusual for rheumatology patients but not for dermatology patients because the skin needs to be examined. Then they are seen by a rheumatology fellow and a dermatology resident together, who go over the history, followed by targeted physical exams. The rheumatology fellow does a general medical examination with a focus on the joints and muscles. The dermatology resident assesses the skin to see how tight it is and to look for other specific skin markers of scleroderma.

After the trainees report their findings to Chung and Fiorentino and they come up with a reasonable plan, all four physicians go into the patient’s room, where, Fiorentino says, “we confirm important parts of the history with the patient, briefly examine the skin, and point out to trainees any unusual findings that might be helpful either diagnostically or prognostically. Patients often have a list of questions, as they’ve waited three or four months, and they’ve often traveled very far for the appointment.”

“At the end of the visit,” Fiorentino says, “Dr. Chung and I always bring up that we do research in the disease. We explain why it’s important to study actual patients and that complex rheumatic diseases are poorly modeled in the laboratory. We stress how rare their disease is and that this is an opportunity to turn the pain and suffering of their disease into something profoundly important and positive. When the patients better understand this perspective, 95% of them agree to be part of our research cohort and donate tissue.”

Lori Chung, MD (second from left), consults with (from left) resident Steven Mason Ronilo, MD; professor of dermatology David Fiorentino, MD; and resident Lucy Liu, MD

Internal Organ Involvement

Treatment for systemic sclerosis depends on what organ systems are involved. There’s quite a bit of data supporting the use of CellCept, an anti-rejection medication, to slow the progression of skin tightening; methotrexate can also be used. Chung uses CellCept more frequently because it helps both the skin and the lungs, whereas methotrexate doesn’t tend to help the lungs. Chung says that “clinical trials primarily target the skin, the lungs (in terms of interstitial lung disease and pulmonary hypertension), and the vascular system in terms of Raynaud’s phenomenon and digital ulcers. Most clinical trials are focused on those aspects of the disease because they’ve been best studied.”

There are many treatment choices for Raynaud’s disease, including drugs like calcium channel blockers that improve blood flow and other vasodilating therapies that are approved for pulmonary hypertension, such as sildenafil.

Chung says this is an exciting time to be involved in clinical trials for systemic sclerosis. “We now have two drugs approved for scleroderma lung disease: An antifibrotic drug called nintedanib was approved in 2019, and the anti-interleukin-6 biologic tocilizumab received FDA approval in March 2021. Stanford was involved in the clinical trials for both of these agents.”

Because of the extent of possible internal organ involvement in systemic sclerosis, Chung points out, there is a critical need for collaborations across the Department of Medicine to care for these patients. She explains their roles: “We work closely with pulmonologists for both interstitial lung disease and pulmonary hypertension in our patients. We also work closely with GI and cardiology. Because we have patients who have severe disease in their blood vessels, we work with a hand surgeon who does sympathectomies on these patients.”

“We stress how rare their disease is and that

this is an opportunity to turn the pain and

suffering of their disease into something profoundly

important and positive”

“We stress how rare their disease is and that

this is an opportunity to turn the pain and

suffering of their disease into something profoundly

important and positive”

For some patients with end-stage interstitial lung disease and/or pulmonary hypertension, lung transplant is an option. For such patients, says Chung, “we engage closely with colleagues from the division of pulmonary, allergy & critical care medicine. Because of the significant GI issues, lung transplants in patients with systemic sclerosis can be complicated by aspiration pneumonia, and therefore patients must meet certain criteria to be eligible for this procedure. Hematopoietic stem cell transplantation is reserved for patients with severe progressive systemic sclerosis. We have established a protocol in conjunction with colleagues from the blood and marrow transplantation & cellular therapy division, and in March 2021 we transplanted our second patient with systemic sclerosis.”

While systemic sclerosis is not exactly a genetic disease, there can be some predisposition. “We think there has to be some sort of trigger for the disease to actually come on,” says Chung, “and one potential trigger is cancer. We think there is immune surveillance going on in the body, where the body is trying to shut down the cancer, which is sometimes successful and sometimes not. That’s when we can see that there’s a cancer associated with the onset of systemic sclerosis or dermatomyositis.”

Chung continues, “Certain autoantibodies are associated with a higher risk of cancer in systemic sclerosis or dermatomyositis. This makes us believe that your immune cells are reacting to an antigen that is similar to a cancer antigen, and that develops antibodies in reaction to potential cancer. The autoantibody associated with cancer in systemic sclerosis is RNA polymerase III. These patients tend to have really bad skin tightening and are also at risk for developing kidney involvement, called scleroderma renal crisis. ACE inhibitors are the mainstay of treatment for scleroderma renal crisis and have greatly reduced the number of patients who have to go on dialysis.”

While systemic sclerosis is both difficult to diagnose and difficult to treat, involving such a vast assemblage of experts across the Department of Medicine improves both the access and the outcomes of patients at Stanford.

Fine-Tuning Medications for Stronger Veteran Hearts

by | Feb 26, 2024 | 2021, all stories 2021

Fine-Tuning Medications for Stronger Veteran Hearts

Fine-Tuning Medications for Stronger Veteran Hearts

Cardiologists have learned over the past 30 years that patients with heart failure benefit the most from taking four classes of medications at the optimal dosages. Despite this, a third or more of patients living with this disease are not prescribed these evidence-based therapies at all, and many others receive prescriptions at suboptimal dosages. It’s a huge problem, even among the heart failure patients seen at the Veterans Affairs (VA) Palo Alto Health Care System, where a minority of heart failure patients take the fully recommended doses of these medications known to improve health and lengthen lives.

To try to turn that around, a collaboration between Stanford and the Palo Alto VA beginning in late 2019 tested a new approach to have pharmacists upwardly adjust, or titrate, patients’ doses for maximum benefit. The population health project brings together an interdisciplinary team of cardiologists, primary care physicians (PCPs), nurses, heart failure researchers, and pharmacists. Veterans in the program work with clinical pharmacists over several visits and calls to get to their optimal dosages.

“We get to leverage Stanford researchers’ expertise on new, cutting-edge interventions to more quickly implement evidenced-based treatments” at the VA, says Rhonda Hamilton, MD, MPH, clinical assistant professor of primary care and population health and general medicine clinic section chief at the Palo Alto VA, who is overseeing the project’s expansion at the Palo Alto clinic site. Under the mentorship of Nazima Allaudeen, MD, clinical assistant professor and director of quality improvement for inpatient medicine at the Palo Alto VA, Justin Slade, MD, led the pilot project while he was a cardiology postresident at Stanford as well as the Physician Scholar for Quality and Safety at the Palo Alto VA. The pilot project focused on the Major General William H. Gourley VA-DoD Outpatient Clinic, typically known as the Monterey VA site.

Maryn Yamamoto, pharmacist; Rhonda Hamilton, MD; Jessica Tran, pharmacist; Lauren Hamilton, data analyst

After just five months of the pilot project, patients on average significantly increased their dosages of both beta-blockers, which slow heart rate, and ACE inhibitor–like drugs, which lower blood pressure. In addition, the numbers of patients at or above 50% of the recommended doses for both drugs have steadily increased since the program began at the VA’s Monterey site. Due to that success, the program was expanded to three more Palo Alto VA sites.

“In the VA system, we have a responsibility not just to fix patients up in the hospital and send them home, but also to keep them healthy for the rest of their lives,” says Slade.

Undertreated Hearts

Heart failure affects 6.2 million adults in the U.S. and nearly 2,000 people across the Palo Alto VA system.

One of the first lines of treatment is to put patients on four different classes of medications. Taken together, these drugs work to reverse the hormonal signals in response to heart failure that tell the heart to work harder, and they reduce pressures in the heart to allow heart function to stabilize and get stronger.

Slade explains that cardiologists have long known that the optimal dosages of the four recommended drug treatments help people live better and longer with heart failure. “But the real challenge is getting those treatments to people in a more consistent, reliable way,” says Allaudeen.

Alex Sandhu, MD, MS

There are many barriers to optimal dosing, including 30-minute clinic appointment windows, during which a cardiologist or PCP must cover previous and current health issues, physician concerns, patient concerns, and a review of the 10 or more medications that veterans on average take, says Hamilton.

Alex Sandhu, MD, MS, instructor of cardiovascular medicine and the heart failure researcher advising the project, says that physician inertia can be another barrier when a patient’s condition appears stable. “Even among stable patients, the risk of deteriorating and getting sicker is substantial,” he says.

By harnessing data from a new VA heart-failure patient dashboard, the team can identify which patients are taking less than the recommended doses of beta-blockers and ACE inhibitor–like drugs. “The dashboard is also an important tool in addressing health care disparities,” says Allaudeen, because it can identify patients who are not coming in as frequently by their data, rather than relying solely on physician referrals.

Among approximately 1,400 patients with heart failure, the team found that fewer than half were taking the drugs at a dosage that was at least 50% of the recommended dosage. (They use 50% or greater as the mark for the recommended dosage because not all patients can tolerate 100%.)

Because heart failure is progressive and the drugs’ effects are additive, getting patients to the highest tolerable doses is key: “The maximum tolerated dose is where these patients will get the most benefit,” says Slade.

Problem-solving Pharmacists

To titrate to that maximum dose, however, normally requires visits to the doctor’s office every two weeks for several months. Very few physicians have the bandwidth to handle that many visits, and many VA patients live far away or lack transportation.

Instead, the team tested the new approach with clinic pharmacists handling these iterative visits, following a cardiologist’s protocol to titrate doses and do follow-up appointments by phone or video call. During the five months of the study, which concluded in April 2020, patients on average improved their beta-blocker doses from 19% to 35% of the recommended dose, and their ACE inhibitor–like doses increased from 52% to 81% of the recommended dose.

“We want our patients to be on the best medical

therapy for heart failure. Every month or year

that goes by that a patient isn’t, that’s a missed opportunity”

“We want our patients to be on the best medical

therapy for heart failure. Every month or year

that goes by that a patient isn’t, that’s a missed opportunity”

“The pilot was definitely a great success to demonstrate that pharmacists were able to successfully increase patients’ doses and safely improve treatment,” says Sandhu. Importantly, there were no safety events or emergency room visits associated with the dosage changes. Sandhu will continue to advise the expanded project on incorporating newer therapies and formally evaluating the program’s impact.

Allaudeen, who cares for patients at the end stages of heart failure in the hospital, says that projects like this are a big win for everyone—for the facility in lowering costs, for the care teams who can treat patients more effectively, and for the patients themselves. The next step is to expand the program to all eight VA clinic sites, with programs currently started in the San Jose, Livermore, and Palo Alto sites.

Allaudeen feels an urgency to get there: “We want our patients to be on the best medical therapy for heart failure. Every month or year that goes by that a patient isn’t, that’s a missed opportunity.”

Taking Racial Disparities to Heart

Rhonda Hamilton was looking for ways to make a real difference in Black and Latinx VA patients’ lives, and she saw an opportunity after the death of George Floyd and the national resurgence of the Black Lives Matter movement.

“I wanted to leverage my leadership position to help with the health care disparities facing Black and Latinx patients in our medical care,” says Hamilton. So she formed a VA committee, and with her teenage daughter Lauren as their research assistant, they found striking results for heart failure: In the United States, “Black patients with heart failure symptoms were far less likely to be on the recommended doses of medications compared to their white counterparts,” says Hamilton.

The new approach to optimizing heart failure medications brings the added bonus of addressing this large racial health care disparity.

“Studies like this one save lives” in tangible ways, says Hamilton. Through her research on health disparities, Hamilton’s daughter Lauren also came to a striking conclusion: Interventions that better meet the needs of Black patients help all patients. And that, Hamilton says, makes the program a win for all veterans and their doctors.

Personal Experience Motivates Tian Zhang’s Work With AML Patients

by | Feb 26, 2024 | 2021, all stories 2021

Personal Experience Motivates Tian Zhang’s Work With AML Patients

It would be enough for a young physician-scientist to tackle the challenge of an extremely aggressive disease like acute myeloid leukemia (AML) while setting up a translational research program, but Tian Zhang, MD, PhD, is doing all that and more.

The new assistant professor of hematology has a young child with an exceptionally rare genetic disorder, but she has found a way for her son’s medical condition to motivate her in her work.

Zhang’s story begins after extensive basic science training, which led to a doctorate in cellular and molecular immunology. A desire to become a physician-scientist prompted her to attend medical school after earning her PhD. During a clinical rotation in year three she became aware of AML, which she says is “the most aggressive and most common kind of acute leukemia in the elderly.”

Zhang’s work with an AML patient showed her firsthand how dramatically the disease presents, as well as its very poor prognosis in most patients, with few treatment options. As part of a huge medical team following a complicated care plan for the AML patient, she was drawn to the disease both intellectually and emotionally, and she chose it for her clinical focus.

She didn’t know it at the time, but the bedside observations she made during both medical school and internal medicine residency would be of great value after she came to Stanford in 2014 for a hematology/oncology fellowship. As a fellow, she witnessed the work that hematology division chief Ravi Majeti, MD, PhD, was doing in the molecular characterization and therapeutic targeting of leukemia stem cells in AML.

“As a translational physician-scientist, I picked Dr. Majeti’s lab to do my postdoc work, and that’s where I took my bedside observations and created a preclinical model so we could study how an experimental treatment would affect human AML cells that were injected into mice,” she says.

Tian Zhang, MD, PhD, with her family

Motivated by Firsthand Experience

While in the midst of her postdoctoral work in Majeti’s lab, Zhang’s life took a dramatic turn when she learned that Isaac, her 4-month-old son, had spinal muscular atrophy (SMA) type 1 (also called Werdnig-Hoffmann disease). Children with SMA type 1, which is characterized by muscle weakness, are not expected to survive past early childhood.

“Obviously that was devastating,” Zhang says after a heavy sigh.

“People with the best of intentions gave me a lot of advice. Most said I should stop working and take care of my 2-year-old daughter and my sick baby, but I took a different track and immersed myself in my work.”

Zhang questioned whether that was a coping mechanism, but she believes it was more likely something else.

“I wasn’t much of a drug developer, to be

honest, before all of this happened to Isaac, but

when I personally witnessed what could come from

the type of research I was performing, I recommitted

myself to working on a rare disease”

“I wasn’t much of a drug developer, to be

honest, before all of this happened to Isaac, but

when I personally witnessed what could come from

the type of research I was performing, I recommitted

myself to working on a rare disease”

Groundbreaking Drugs

What happened—and what would have made a lifesaving difference to so many other babies before Isaac—was that he received three first-in-human drugs from the time he was 4 months old.

Just a year before Isaac’s birth, there was no treatment at all for SMA type 1. Then, the drug Spinraza was approved, and specialists prescribed it for Isaac to keep the disease from progressing.

The following year, Isaac received another breakthrough treatment—the first gene-replacement therapy to correct a genetic deficiency that was lethal in babies—which improved his condition.

And in August 2020, he received a third FDA-approved treatment, risdiplam, for SMA type 1, which furthered his improvement.

“I am a scientist at heart, and I know all the details of how long it takes for a drug to become available. So when I saw firsthand the direct benefit that Isaac received from people like me who were working on rare diseases and invested in drug development, it actually motivated me.

“I wasn’t much of a drug developer, to be honest, before all of this happened to Isaac, but when I personally witnessed what could come from the type of research I was performing, I recommitted myself to working on a rare disease,” Zhang says.

Investigator-Initiated Trial

Success from her preliminary research led her to suggest repurposing the drug enasidenib for use in a variety of blood disorders. For more than a year, she offered her concept to pharmaceutical companies before she reached an agreement with Celgene for the Bristol-Myers Squibb subsidiary to fund her investigator-initiated trial.

Typically a pharmaceutical company develops its own drugs, and the company will approach an institution like Stanford to perform a study because of the drug’s promise for patients with a particular disease. This is known as a sponsored trial.

“We have many sponsored trials in the division of hematology, but we didn’t have many of these home-grown or home-investigated projects like mine that clearly could have clinical benefit,” she explains.

AML Translational Research Program

Zhang, who was appointed assistant professor of hematology in March 2020, is now working to establish an independent research program focused on translational research in AML. She’s collaborating closely with Majeti and Gabriel Mannis, MD, another AML physician and assistant professor of hematology, to link the lab and the clinic.

“The goal of this translational program in AML is to bridge the gap between basic laboratory scientific research and clinical trials, but equally importantly to take observations from the clinic back to the lab. A major focus will be on developing investigator-initiated trials at Stanford,” Majeti says.

Leaders of the translational program see the chance to create a better pathway for scientists who work on the bench, allowing them to engage with clinicians who are on the front lines of patient care. The program should allow them to exchange ideas for new research projects that can be developed with the eventual aim of translating them back into the clinic.

As a physician-scientist who’s been working in the Majeti lab as well as taking care of patients both in the clinic and on the inpatient side, Zhang is uniquely positioned to help both sides.

“Tian is the perfect person to head up our AML translational research program, as she is accomplished in both laboratory research and clinical care of AML patients,” says Majeti. “She knows exactly how basic investigation can be applied in the clinic and equally how clinical observations can be explored in the lab.”

While Zhang is building her program for translational science with an initial focus on AML, the broader goal is to expand into other diseases. “In fact, as we develop the AML program, we are building infrastructure that can be applied to research for other kinds of blood disorders,” she says.

“I’ve become a huge advocate for drug development because I now realize the benefit that patients can derive from new treatments that are coming up through translational research,” she adds.

How is Isaac today?

“Now he is 3 and doing things that I never imagined he would do,” she says.

Innovative Antibody Treatment Proves Safe and Effective for Immune Disorders

by | Feb 26, 2024 | 2021, all stories 2021

Innovative Antibody Treatment Proves Safe and Effective for Immune Disorders

Many blood and immune disorders could be cured by transplanting healthy blood stem cells from a matched donor. But first the patients need a pretreatment procedure to eliminate their own blood stem cells, making room in the bone marrow for the donor cells to take their place.

The problem is that the standard pretreatments—chemotherapy or radiation—are very toxic. Doctors don’t want to give them to vulnerable children, such as those with a rare genetic disorder called severe combined immunodeficiency (SCID).

Infants with SCID have compromised immune systems that struggle to fight off even common infections caused by viruses and fungi. These babies have many chronic and life-threatening problems, including frequent lung infections, chronic diarrhea, and recurrent sinus infections.

Judy Shizuru, MD, PhD, reviews data with Wendy Pang, MD, PhD

“Without treatment, SCID infants usually die from infections within the first two years of life. Blood stem cell transplants are the only definitive cure for this disease,” says Judith Shizuru, MD, PhD, professor of blood and marrow transplantation and cellular therapy and of pediatrics. “But transplants usually involve chemotherapy, and we don’t want to give these agents to these children because they’re particularly susceptible to the damaging short-term and long-term effects—including growth defects, neurological problems, and increased risk of cancers. This is especially true for certain subtypes of SCID.”

Instead, SCID patients are often given a blood stem cell transplant without pretreating with chemotherapy to create space in their bone marrow. But then the donors’ self-renewing blood stem cells may not fully engraft, so the kids can’t robustly regenerate their immune systems. These children have to rely on regular intravenous immunoglobulin infusions to boost their immune response, and the effectiveness of donor immune cells can wane over time.

The great need for a less toxic pretreatment for blood stem cell transplants inspired Shizuru to initiate a Stanford study testing a novel antibody pretreatment in SCID patients—in collaboration with Rajni Agarwal-Hashmi, MD, associate professor of pediatrics, and other stem cell transplantation and regenerative medicine specialists at Stanford and UC-San Francisco.

Targeting Blood Stem Cells

The novel pretreatment uses the JSP191 antibody to target a protein called CD117, found on the surface of blood stem cells. The antibody binds to this protein, which then blocks CD117 from binding to a stem cell factor critical for keeping blood stem cells alive. When the interaction between CD117 and the essential stem cell factor is interrupted, the patient’s blood stem cells are depleted—making space for the donor’s healthy cells to engraft.

“It’s not like chemotherapy or radiation,” says Shizuru. “It’s a targeted way to deplete the blood stem cells without damaging normal healthy cells.”

The Stanford team chose SCID patients for their first human JSP191 clinical trial in part because these children have a unique biology—they lack lymphocytes, so they are less likely to immunologically reject the blood stem cells from a donor. Since immune suppressive medications aren’t necessary, the researchers can more easily see if the antibody therapy clears space in the bone marrow and the transplant works.

Initially, the clinical trial studied older children and adults with SCID whose first blood stem cell transplant had failed, so that they could evaluate whether JSP191 therapy was safe and well tolerated. The participants ranged in age from 3 years old to mid-30s, but most were between 11 and 13 years old. According to Shizuru, many of these kids had chronic infections and also wanted to be liberated from having intravenous immunoglobulin infusions.

Rajni Agarwal-Hashmi, MD

Rajni Agarwal-Hashmi, MD

Promising Results

The results are very promising, as Shizuru reported in 2019 at the American Society of Hematology annual conference. The antibody safely created room in the patients’ bone marrow, allowing healthy donor stem cell engraftment without common side effects like transfusion reactions, treatment-related toxicities, or bone marrow suppression.

“The wonderful thing about the antibody JSP191 is it’s super-safe. This conditioning agent doesn’t affect the DNA or any other organ, as far as we can tell,” explains Shizuru. “We give it as a onetime, really low dose. And it’s not showing any side effects. It’s an amazing drug.”

The study’s clinicians even remarked that the re-transplant kids looked bored in the hospital because the expected complications didn’t happen, says Shizuru. “The patients’ counts didn’t drop. They didn’t have increased infections. They didn’t need blood transfusions,” she says. “So, we decided to give the antibody as an inpatient treatment and then do everything else as outpatient after 48 hours.”

The results were promising from the start. The first participant pretreated with JSP191 was a 3-year-old girl with chronic diarrhea and infections. After about a year, she no longer had diarrhea and started going to school for the first time. In fact, her family was infected with COVID-19 and she did fine, as Shizuru learned during a public discussion.

Expanding the Clinical Trial

Based on the safety and success of the first phase, the JSP191 trial expanded to include infants newly diagnosed with SCID. Two infants have received the antibody pretreatment followed by a blood stem cell transplant.

The first infant did really well, demonstrating signs that his donor cells may fully restore his immune function. The second infant’s response was more complicated; the researchers determined that she had some immune function that may have rejected the maternal stem cells. She subsequently underwent another transplant without the antibody agent, using a mix of chemotherapies.

After their initial success, Shizuru’s team expanded the use of JSP191 to include other vulnerable populations—older adults with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). AML is a type of leukemia in which DNA mutations cause the rapid growth of abnormal cells that build up in the bone marrow. Although it starts in the bone marrow, AML often quickly moves to the blood and sometimes spreads to other parts of the body. MDS are a group of diverse bone marrow disorders in which the bone marrow does not produce enough healthy blood cells. Both AML and MDS primarily occur in people over 65 years old.

“It’s not like chemotherapy or radiation. It’s a

targeted way to deplete the blood stem cells

without damaging normal healthy cells”

“It’s not like chemotherapy or radiation. It’s a

targeted way to deplete the blood stem cells

without damaging normal healthy cells”

This adult study is based on the preclinical work of Wendy Pang, MD, PhD, who was a postdoctoral fellow in the Shizuru laboratory. She showed that the disease-causing MDS and AML stem cells express CD117, so they can be targeted by JSP191. Further, the team observed synergistic eradication of stem cells when these anti-CD117 antibodies were combined with low-dose radiation.

The ongoing clinical trial utilizing JSP191 combined with low-dose radiation is led by Lori Muffly, MD, assistant professor of blood and marrow transplantation and cellular therapies. The preliminary results are encouraging based on the first six participants, who were older adults (64–74 years old) with AML or MDS. The researchers observed no side effects associated with JSP191, and the patients’ blood stem cell transplants were successful.

“We transplanted our first SCID babies and then opened the trial up to older patients with AML and MDS. So, now we’re covering the full spectrum for this targeted therapy: from a 3-month-old infant with SCID to a 74-year-old with AML,” Shizuru says.

The JSP191 project has now moved to a biotechnology company, Jasper Therapeutics, which Shizuru founded and Pang now works at. Shizuru expects that in the future, the studies will expand to include sickle cell disease, a group of inherited red blood cell disorders, where the JSP191 antibody can help to engraft the donor cells.

“In terms of pretreatment, there’s been no innovation on transplant agents in decades. People have been innovating on transplant by simply reducing the dose of chemotherapies, but we haven’t seen a successful new agent,” explains Shizuru. “The development of JSP191 leverages our understanding of the biology of blood stem cells by targeting a critically important molecule. JSP191 antibody is now the platform agent.”

‘Born to Be Bad’: Cancer Researcher Christina Curtis Presses for Answers on the Origins of Tumors

by | Feb 26, 2024 | 2021, all stories 2021

‘Born to Be Bad’: Cancer Researcher Christina Curtis Presses for Answers on the Origins of Tumors

Christina Curtis, PhD

Christina Curtis, PhD

‘Born to Be Bad’: Cancer Researcher Christina Curtis Presses for Answers on the Origins of Tumors

Through all the discoveries that cancer researcher Christina Curtis, PhD, has made so far, there has been one big-picture question driving her forward. It has preoccupied Curtis since she was a curious high school student who lost her grandfather to the disease.

How does a tumor begin?

While scientists proved decades ago that cancer begins with genetic mutations that allow malignant cells to develop different characteristics than other cells, the exact process of how the tumor begins—and which cells acquire those mutations—is still poorly understood, says Curtis, associate professor of oncology and genetics, director of breast cancer translational research, and co-director of the Molecular Tumor Board at the Stanford Cancer Institute.

“What does it take to form a cancer?” Curtis asks. “We’re beginning to have the tools and technologies, both experimental and computational, to start to address that. There’s so much potential.”

To discover the origins of cancer, Curtis and her colleagues are working to trace the life cycle of a tumor, beginning with the first error in a cell’s DNA, to the point where it spreads, or metastasizes, to other organs. The Curtis laboratory analyzes patient tumor samples, creates virtual tumors that simulate the process in a human being, and grows miniature versions of organs—called organoids—on which the scientists can use CRISPR gene-editing technology to introduce alterations that are common in certain cancers and observe what it takes for a tumor to develop.

A New Era in Breast Oncology

While Curtis has made contributions across a number of areas in oncology research, she may be best known for her discovery of 11 genetically distinct subgroups of breast cancer. This work, published in Nature in 2012, has formed a key pillar of the Curtis lab’s work, culminating in a landmark 2019 Nature paper showing that four of these subgroups have a high risk of late metastasis and collectively account for about 25% of women whose tumors express the estrogen receptor and not the HER2 receptor. In some cases, the recurrence comes decades after the women thought they were cured.

Allison Kurian, MD, MSc, professor of oncology and of epidemiology and population health and director of the Stanford Women’s Clinical Cancer Genetics Program, says she can’t think of another scientist who has made such advances in the field of breast oncology so early in their career.

“Dr. Curtis is a brilliantly original thinker whose work has already begun to have a transformative impact on the field of breast oncology,” says Kurian. “Late recurrence of favorable-diagnosis, hormone receptor–positive breast cancer is a problem of tremendous importance, affecting thousands of women annually. Dr. Curtis’ discovery of molecular drivers of this disease offers excellent potential for the development of targeted therapies.”

“Dr. Curtis is a brilliantly original thinker

whose work has already begun to have a transformative

impact on the field of breast oncology”

“Dr. Curtis is a brilliantly original thinker

whose work has already begun to have a transformative

impact on the field of breast oncology”

This work has led to a Department of Defense–funded clinical trial, of which Curtis is the principal investigator, together with George Sledge, MD, professor of oncology, to test new therapies for these high-risk breast cancer patients. The trial is being led by Sledge and Jennifer Caswell-Jin, MD, assistant professor of oncology, who trained in Curtis’ lab. It will be the first of what Curtis believes will be many trials that could help usher in precision medicine for this biomarker-defined group of cancer patients.

The Quest Becomes Personal

Curtis knows from personal experience that these discoveries can’t come fast enough. In 2017, when Curtis was in the throes of deep thinking about the problems of metastasis and late-stage cancers, her parents were diagnosed with different cancers one month apart. Her mother lived just three and a half months; her father recovered, but Curtis worries about recurrence.

The experience pushed Curtis to place even more focus on tracing a tumor’s starting points.

She was the mother of two young children, facing two parents sick with cancer, and it was all happening so fast.

We were doing research on late-stage cancers—and had made really important insights there—but the whole experience impressed on me a renewed need to intercept earlier,” Curtis says. “It’s not enough to detect a tumor when it’s already metastasized.”

Seeds of Metastasis Start Early

The lab’s recent findings have reinforced the message that metastasis can happen earlier than previously suspected.

One study, published in Nature Genetics, expanded on Curtis’ 2019 discovery that some tumors are “born to be bad.” She and colleagues coined the term after observing that in most patients with metastatic colorectal cancer, the cancer cells spread to distant organs, like the brain or liver, years before the initial tumor was diagnosed.

In the new paper, she and her collaborators showed that early metastasis can happen in breast and lung cancer too, two to four years before the first tumor is detected—illuminating the need for improved strategies to detect cancers earlier. What’s more, their findings illuminated the need to consider the timing and types of therapy to avoid the emergence of drug resistance.

While these are not easy messages to convey, and more research is needed, “they open our eyes to the need to study patient tumors sampled during the course of therapy, and to anticipate resistance,” Curtis says. “The seeds of metastasis can be sown early, and we need to study the continuum of disease with this in mind. It can empower the field to address some of those harder questions, particularly as new technologies are at hand.”

Recently, Curtis and colleagues also identified a long-sought-after biomarker for women with early-stage, newly diagnosed, HER2-positive breast cancer. Up to 50% of patients with HER2-positive tumors, which produce too much HER2 protein, have residual cancer following treatment.

“Many clinical trials have been designed with the goal of asking, ‘Is there a new biomarker that would predict which women would respond to therapy, above and beyond the fact that they have HER2 amplification?’ and the field has struggled,” Curtis says. “It’s unfortunate, because here’s a place where we have multiple FDA-approved drugs, and we could either combine them to increase a women’s response, or we could give targeted therapy and leave out the chemo and spare this patient the additional toxicity. So we really need predictive biomarkers.”

In a study that deployed a completely new technology called digital spatial profiling to look at 40 different tumor and immune proteins in tumor tissue samples before and during preoperative therapy, Curtis and colleagues found what they were looking for. Patients who had higher levels of an immune marker called CD45 after just a single cycle of HER2-targeted therapy tended to have a dramatic response to treatment, while those with lower levels did not. The findings were published in April 2021 in Nature Cancer.

The next step will be to design a clinical trial that tests these findings.

“If it validates, this has the potential to transform patient care,” Curtis says. “We would be able to personalize therapy with this approach—for example, by eliminating chemotherapy use in a subset of patients who do not require it.”

A Dedicated Mentor

Besides her notable scientific contributions, Curtis is known as a “deeply collaborative” colleague and “gifted lecturer, with exceptional skill in mentoring young investigators,” Kurian says. In particular, Curtis, who had few female mentors when she trained in computational biology, has made an effort to create an environment where women feel supported. Today, more than half of the scientists in her lab are female.

“I’ve had the opportunity to train many stellar trainees that have gone on to be faculty and lead new breakthroughs,” Curtis says. “It’s been really important to me to try to cultivate a laboratory where everybody felt that they had an equal footing, and especially make sure that female scientists felt they could do this whether they wanted to have a family or not.”

Caswell-Jin says she felt lucky to work in Curtis’ lab.

“She is an extraordinary mentor,” Caswell-Jin says. “She cares deeply about the science we work on together and about the potential for it to translate to the clinic to improve people’s lives. She loves helping us grow from trainees in her lab to colleagues and collaborators.”

Eliminating the ‘Chronic’ from COPD

by | Feb 26, 2024 | 2021, all stories 2021

Eliminating the ‘Chronic’ from COPD

People who have chronic obstructive pulmonary disease (COPD) have it forever; that’s why it’s called “chronic.” Though it can be managed, it can’t be reversed. The only known cure is a lung transplant. And though the primary cause of COPD is cigarette smoking, growing evidence is showing that environmental factors such as air pollution are also triggering the disease.

Department of Medicine researchers are taking on this disease with new vigor, and they are uncovering potential pathways for recovery, or at least for improved outcomes, for COPD.

Lauren Eggert, MD, shows a patient how to use a mobile spirometer

Undiagnosed COPD a Key Focus

In the United States, an estimated 16 million people have been diagnosed with COPD. But it is estimated that an additional 8 million may have undiagnosed COPD, putting them at risk for onset of symptoms such as shortness of breath and severe coughing or wheezing.

Researchers are trying to find easy, cost-effective, accessible ways to diagnose more people with COPD so that physicians can intervene earlier and prevent both morbidity and unnecessary costs to the health system. According to Lauren Eggert, MD, clinical assistant professor of pulmonary, allergy, and critical care medicine, “There is growing evidence confirming that COPD is underdiagnosed by at least 50% (and as high as 78% in some studies).”

Much of this undercounting has to do with the lack of routine screening. “A simple procedure called spirometry could easily be incorporated into an annual physical exam,” notes Eggert. “It takes just a couple of minutes to perform and can reveal vital, lifesaving information about the patient and whether or not they have COPD.” That information could be used to develop a plan of care. Though this approach wouldn’t eliminate the disease, it could enable the patient to begin treatment sooner than if advanced COPD were detected because of a life-threatening event.

While the U.S. Preventive Services Task Force (USPSTF), which develops screening guidelines, does not currently recommend screening for COPD, the American Thoracic Society has suggested that this may need to be reevaluated.

“This is an important step forward in tracking down this disease,” says Eggert. She is currently creating a plan to study how inexpensive mobile spirometry units in the primary care setting could identify undiagnosed individuals with COPD.

“There is growing evidence confirming that

COPD is underdiagnosed by at least 50%

(and as high as 78% in some studies)”

“There is growing evidence confirming that

COPD is underdiagnosed by at least 50%

(and as high as 78% in some studies)”

Reversing or Preventing Lung Damage

“It would be great if alternative therapies and treatments were available for COPD,” muses lung transplant specialist Shravani Pasupneti, MD, instructor of pulmonary, allergy, and critical care medicine at Stanford. “Right now, lung transplantation is the only cure for patients with end stage COPD. While it is helpful for some, it has limits and is not a viable option for everyone.”

Pasupneti took one small step closer to achieving that goal with research reported in 2020—the first time anyone at Stanford had published basic science research about COPD. She showed that genetically knocking out a transcription factor called HIF-2 alpha in mice led to COPD, and that increased HIF-2 prevented the disease. Given that cigarette smoke decreases HIF-2 alpha, this finding has important real-world applications and could be used to develop new therapies. She hypothesizes that HIF-2 alpha is a central regulator of lung health, and therapies that manipulate its expression could be used to treat COPD. Pasupneti is now embarking on studies to find the appropriate pathways for this process.

“The overall direction of our work,” comments Pasupneti, “is to find the mechanism of action of HIF-2 alpha in the development of COPD, with a goal of developing better therapies to treat (and ideally prevent) the disease.”

This important work demonstrates the close link between laboratory research and patient care that is the hallmark of Stanford Medicine.

Unique Offerings Help Patients Cope With COPD

“At a big medical center like Stanford, we have the resources to provide aggressive management of COPD,” says Eggert. This includes pulmonary rehabilitation programs, nutrition counseling, and comprehensive medication management.

Often, the upper section of a COPD patient’s lungs stops functioning, which makes breathing more challenging. Air can get in, but the patient can’t expel it. Physicians at Stanford can insert mechanical valves to block off airflow entirely to the top part of the lungs.

“At a big medical center like

Stanford, we have the resources to

provide aggressive management of COPD”

“At a big medical center like

Stanford, we have the resources to

provide aggressive management of COPD”

Working with medical residents, Eggert is developing a digital educational tool to teach patients how to use an inhaler. “There are many types of inhalers, and they’re all different,” she notes. “They’re not intuitive. We want to work with patients before they leave the hospital to make sure they understand how to use theirs.” With an iPad or computer, patients will be able to check on their continued correct use of the inhaler once they get home.

It’s Not Easy

Of course, the most effective step that a patient with COPD can take is to stop smoking. Though this won’t reverse the damage that’s already been done, it will certainly stop its progression.

“But I understand that it’s really hard to do,” says Eggert. “It’s like dieting: It’s easy to tell someone to do it, or to know yourself that you should, but it’s very difficult to break the habit.”