Nav: Home

Personalized cell therapy combination achieves complete remission in CLL patients

May 31, 2017

PHILADELPHIA - Combining the kinase inhibitor ibrutinib with an investigational personalized cellular therapy known as CTL119 can lead to complete remission in patients with high-risk chronic lymphocytic leukemia (CLL), according to new research from the Perelman School of Medicine at the University of Pennsylvania and Penn's Abramson Cancer Center (ACC). The team will present the results from its pilot study of this combination therapy during the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract # 193355).

The team will present on the first 10 patients in the trial, each of whom had been taking ibrutinib for at least six months but had not achieved a complete remission. They were then infused with their own engineered "hunter" T cells. Eight of nine patients who are evaluable for response had no evidence of disease in their bone marrow at three months, and all remain in remission after a median follow-up period of six months, with a range from 0.5 to 9 months. One patient was found to have a partial response in their marrow.

The research team is led by Carl June, MD, the Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine and director of Translational Research in the ACC, along with David Porter, MD, the Jodi Fisher Horowitz Professor in Leukemia Care Excellence and director of Blood and Marrow Transplantation in the ACC. The data will be presented by the study's first author, Saar Gill, MD, PhD, an assistant professor of Hematology-Oncology.

"Combining ibrutinib with the CTL119 therapy achieved very powerful results for these patients, and with limited toxicity," Gill said. "This newer, coupled approach gives us hope that personalized cell therapies could be an important option for high-risk CLL patients on these types of drugs."

CTL119 manufacturing begins with a patient's own T cells, some of which are removed and then reprogrammed in Penn's Clinical Cell and Vaccine Production Facility with a gene transfer technique designed to teach the T cells to target and kill tumor cells. The engineered cells contain an antibody-like protein known as a chimeric antigen receptor (CAR), which is designed to bind to a protein called CD19 found on the surface of cancerous B cells. The modified "hunter" cells are then infused back into the patient's body, where they multiply and are believed to attack the cancer cells.

Patients in the trial had been on ibrutinib for a minimum of six months and had not achieved a complete response when they received an infusion of engineered cells split over three consecutive days. All had abnormalities of TP53 or ATM - two mutations associated with high-risk disease - and two patients had increasing BTK C481S clones, also a high-risk marker.

The new data builds off several preclinical studies supporting the use of ibrutinib with CAR therapy. In March 2016, Penn researchers published a study in Blood that showed long-term ibrutinib treatment reverses the dysfunction of T cells in CLL and that combining CAR therapy with ibrutinib enhanced engineered T cell proliferation in mice.

CAR therapy alone has led to complete remissions and responses in some CLL patients, but not all patients respond, findings that led the Penn team to seek combination therapies that might enhance efficacy of the therapy. In 2015, Penn Medicine researchers reported in Science Translational Medicine an overall response rate of 57 percent in CLL patients treated with CAR therapy, and a complete remission rate of 29 percent.

Ibrutinib is a well-tolerated, oral drug that improves symptoms and survival in high-risk CLL patients, but is not curative and requires continuous treatment for life. It rarely induces complete remissions by itself. That first year on the drug may provide an optimal window to collect T cells from patients and subsequently administer a potentially curative T cell therapy, the authors said.

"These patients had a lower disease burden and were treated earlier in the course of their disease, which distinguishes it from other studies," Gill said. "One of the challenges in treating CLL patients with personalized cellular therapy is not having healthy enough cells to manufacture. The results suggest that ibrutinib restored T cell activity in the patients.

All 10 patients who received the CTL119 cells experienced mild cytokine release syndrome (CRS), a known potentially lethal type of toxicity, within a few days after receiving their infusions; however, none required treatment with tocilizumab, an immunosuppressant drug that blocks the effects of the inflammatory cytokine IL-6. All recovered from their CRS.

CRS can include varying degrees of flu-like symptoms, with high fevers, nausea, and muscle pain, and temporary neurologic symptoms, including delirium, and in more severe cases, low blood pressure and breathing difficulties which may require treatment in an intensive care unit. One patient in the study developed tumor lysis syndrome and recovered.

Longer follow-up will reveal the durability of these results, the authors said, and may support the evaluation of a first-line approach with ibrutinib and CAR therapy in an effort to remove the need for chronic therapy.
This study was supported by a grant from Novartis.

Editor's note: The University of Pennsylvania has licensed technologies involved in these trials to Novartis. Some of the scientists involved in these trials are inventors of these technologies. As a result of the licensing relationship with Novartis, the University of Pennsylvania receives significant financial benefit, and these inventers have benefitted financially and/or may benefit financially in the future. Additional disclosure information is available in the meeting abstracts.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $6.7 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2016 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2016, Penn Medicine provided $393 million to benefit our community.

For more Penn Medicine news from the 2017 American Society of Clinical Oncology Annual Meeting, visit:

University of Pennsylvania School of Medicine

Related Combination Therapy Articles:

Can a combination immune therapy reduce genital herpes outbreaks?
New Haven, Conn. -- Yale investigators have shown that the combination of a vaccine and a medicated cream is a promising strategy to dramatically reduce the recurrence of genital herpes.
New combination therapy established as safe and effective for prostate cancer
A novel therapy using two targeted treatments for prostate cancer has been shown to maximize efficacy while reducing side effects according to research presented at the Society of Nuclear Medicine and Molecular Imaging (SNMMI) 2019 Annual Meeting.
Combination therapy advisable for bowel disorder IBS
The more abnormalities in intestinal and brain function that IBS sufferers have, the more severe their symptoms of this functional bowel disorder, and the more adversely their everyday life is affected.
CD40 combination therapy can shrink pancreatic tumors
A new combination of immunotherapy and chemotherapy for pancreatic cancer caused tumors to shrink in the majority of evaluable patients.
Combination therapy treats leishmaniasis, HIV patients
Coinfection with visceral leishmaniasis (VL) and human immunodeficiency virus (HIV) has been observed in at least 35 countries on four continents and requires special case management.
Combination gene therapy more effective in cartilage preservation in osteoarthritis
A combinatorial gene therapy approach -- one designed to inhibit inflammation and one targeting protection against cartilage degeneration -- was shown to preserve articular carti-lage better than each approach alone in animal models of both moderate and severe post-traumatic osteoarthritis.
Combination therapy promising against blindness-causing bacterial keratitis
Multidrug-resistant bacterial infections of the cornea are a leading cause of blindness and cannot be effectively managed with current ophthalmic antibiotics.
Novel combination therapy promotes wound healing
By incorporating a gene-suppressing drug into an over-the-counter gel, researchers at Albert Einstein College of Medicine and their colleagues cut healing time by half and significantly improved healing outcomes compared to control treatments.
Combination therapy targets latent reservoir of HIV
In a new study, Dan H. Barouch, MD, PhD, Director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center, and colleagues demonstrate that administering broadly neutralizing antibodies (bNAb) designed to target HIV in combination with agents that stimulate the innate immune system delayed viral rebound following discontinuation of ART in monkeys.
Enhancing immune checkpoint inhibitor therapy using treatment combination
A combination of a novel inhibitor of the protein CK2 (Casein kinase 2) and an immune checkpoint inhibitor has dramatically greater antitumor activity than either inhibitor alone, according to research from The Wistar Institute that was published online in Cancer Research.
More Combination Therapy News and Combination Therapy Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Rethinking Anger
Anger is universal and complex: it can be quiet, festering, justified, vengeful, and destructive. This hour, TED speakers explore the many sides of anger, why we need it, and who's allowed to feel it. Guests include psychologists Ryan Martin and Russell Kolts, writer Soraya Chemaly, former talk radio host Lisa Fritsch, and business professor Dan Moshavi.
Now Playing: Science for the People

#538 Nobels and Astrophysics
This week we start with this year's physics Nobel Prize awarded to Jim Peebles, Michel Mayor, and Didier Queloz and finish with a discussion of the Nobel Prizes as a way to award and highlight important science. Are they still relevant? When science breakthroughs are built on the backs of hundreds -- and sometimes thousands -- of people's hard work, how do you pick just three to highlight? Join host Rachelle Saunders and astrophysicist, author, and science communicator Ethan Siegel for their chat about astrophysics and Nobel Prizes.