Abstract
Juno has sided with St. Jude, from which it agreed in December 2013 to license exclusively St. Jude's U.S. Patent No. 8,399,645, covering a chimeric antigen receptor technology for cancer immunotherapies. The ’645 patent, issued March 19, 2013, lists two co-inventors, Chihaya Imai, MD, PhD, and a former St. Jude investigator, Dario Campana, MD, PhD. Dr. Campana left St. Jude in 2011 to take his current positions as professor in the Department of Pediatrics and principal investigator at Singapore's National University Cancer Institute.
St. Jude contends that UPenn wrongly used material covered by the ’645 patent and two earlier material transfer agreements (MTAs) in the development of its own chimeric T-cell receptor. UPenn has asked the court to declare it had not infringed the patent or the two MTAs, and that the patent was invalid.
Juno was launched in December 2013 with $120 million in series A funding by Memorial Sloan-Kettering Cancer Center, the Fred Hutchinson Cancer Research Center, and Seattle Children's Research Institute. Through its license agreement, Juno is obligated to “join as a party, and control, pursue, and defend” claims related to the two MTAs (Juno Therapeutics, 2013).
Under the first MTA in 2003, St. Jude provided an anti-CD19-BB-zeta chimeric T-cell receptor construct and a related gene sequence to UPenn and Carl June, MD, director of translational research in UPenn's Abramson Cancer Center (
St. Jude alleges UPenn breached the MTAs by discussing commercializing the chimeric T-cell receptor material and by incorporating much of the St. Jude–developed technology without acknowledging St. Jude as the source of material in the anti-CD19 CAR cDNA detailed by the university in two journal articles.
UPenn contends that Dr. June and colleague Michael Milone, MD, PhD, developed a largely different CAR than Dr. Campana's—though the university's director of legal affairs, Kathryn A. Donohue, acknowledged in a letter: “We incorporated the cDNA from Dr. Campana/St. Jude into the vector” (Dalzell, 2013).
UPenn told St. Jude it was ending the MTAs in 2011. A year later, UPenn joined Novartis in launching an alliance to expand use of personalized T-cell therapy. Novartis contributed $20 million toward a Center for Advanced Cellular Therapies with joint R&D focused on discovery, development, and manufacturing of adoptive T-cell immunotherapies.
St. Jude filed a complaint in July 2012 with the U.S. District Court Western District of Tennessee. Eight days later, UPenn filed its own complaint against St. Jude in the district court's Eastern District of Pennsylvania. UPenn contended that St. Jude interfered with the university's prospective contractual relations and denied having breached the MTAs. The cases were consolidated in October 2012, and the tort claim dismissed in April.
In 2003, Dr. Campana presented an article on the anti-CD19 chimeric receptor at an American Society of Hematology conference attended by Dr. June. He followed up with Dr. Campana, who agreed to share “material” consisting of the anti-CD19 BB-zeta chimeric receptor construct, “including any progeny, portions, unmodified derivatives and any accompanying know-how or data,” (Dalzell, 2013).
The 2003 MTA stated that “the material will only be used to create a lentiviral chimeric T-cell receptor construct to be used in pre-clinical studies,” and that UPenn cannot commercialize any product containing the material without the prior written approval of St. Jude. St. Jude and UPenn also agreed to jointly publish research results based on the material (Dalzell, 2013).
UPenn concluded a lentiviral vector—a modified form of HIV-1—was a more effective way to genetically modify human T cells. The university created what it called a modified derivative of Dr. Campana's CAR incorporating the modified anti-CD19-BB-ζ sequence into a lentiviral plasmid created earlier in Dr. June's lab. The university CAR used a primer-based polymerase chain reaction to generate a DNA sequence similar to what Dr. Campana constructed, except to allow recombination into UPenn's lentiviral vector by including five nucleotide differences at the ends of the sequence.
UPenn has argued the material covered by the 2003 MTA did not broadly encompass any and all derivatives of the biological materials provided, while the sequence and the other information did not constitute “know-how” since sequences are readily obtainable by people skilled in molecular biology using common techniques.
St. Jude contends the identical approximately 1,500-base-pair sequence it provided was used by UPenn, except for a single-base-pair difference. The case remained pending at deadline before U.S. District Court judge Stewart Dalzell.
That database may be sufficient for a safety assessment, CHMP told Celladon, if MYDICAR demonstrates a highly significant treatment effect in the advanced heart failure population and assumes that no “untoward” effects are attributed to MYDICAR. CHMP also recommended follow-up of 5 years for patients in the calcium up-regulation by percutaneous administration of gene therapy in cardiac disease (CUPID) 2 study, in accordance with EMA's guideline for gene therapy medicinal products.
“We are very pleased with the feedback from the CHMP,” Krisztina Zsebo, PhD, Celladon's president and CEO, said in an announcement. “Assuming the results from our ongoing CUPID 2 trial are favorable, based on this feedback we believe our CUPID 2 trial can serve as the primary basis for marketing approval of MYDICAR by the EMA, in which case no further phase III studies would be required prior to an MAA submission” (Celladon, 2013).
In the same announcement, Celladon said investigators have initiated the adeno-associated virus type 1 (AAV1)–cytomegalovirus (CMV)–SERCA2a Gene Therapy Trial in Heart Failure (AGENT-HF). The primary objective of AGENT-HF is to determine whether treatment with MYDICAR leads to reverse remodeling of the heart.
AGENT-HF will enroll approximately 44 heart failure patients in France, with half receiving MYDICAR and the other half a placebo. The primary endpoint at 6 months will be changed, compared to baseline, in left ventricular (LV) end systolic volume as measured by cardiac computed tomography.
AGENT-HF is not required by any regulatory authorities for systolic heart failure indications. However, patients enrolled in the trial will be included in the overall safety database submitted in an MAA submission, Celladon said.
Janssen agreed to pay Capricor $12.5 million upfront and up to $325 million if Janssen exercises option rights plus royalties on commercial sales of CAP-1002. Under the agreement, Janssen has the right to enter into an exclusive license agreement for CAP-1002 at any time until 60 days after Capricor delivers 6-month follow-up results from phase II of its ALLSTAR clinical trial for cell therapy.
CAP-1002 is an allogeneic cardiosphere-derived cell therapy under evaluation in patients who have suffered a large myocardial infarction.
“This collaboration with Janssen, one of the world's largest and most respected healthcare companies with a strong presence in cardiovascular and metabolism, is a tremendous milestone for Capricor Therapeutics and an important validation of our lead product, CAP-1002, and the underlying science,” Capricor CEO Linda Marban, PhD, said in a statement (Capricor, 2014).
Capricor has won approximately $19.8 million in funding from California's stem cell agency, the California Institute for Regenerative Medicine (CIRM), toward the phase II trial, through CIRM's Disease Team Therapy Development-Research program. The trial will be designed to assess both safety and efficacy of a heart-derived stem cell product in patients who have experienced a heart attack either recently or in the past.
Capricor told CIRM its phase I data suggests that treatment with the heart-derived cell product under development can turn scar tissue back into healthy heart muscle. The clinical program for CAO-1002 also builds upon earlier research for which Eduardo Marbán, MD, PhD, director of the Cedars-Sinai Heart Institute, won an earlier $5.56 million Disease Team Research I grant from CIRM.
“The planned mid-stage trial will hopefully confirm that finding in a larger patient group and provide additional data to support the safety profile of the product,” the company stated in an abstract of the research published on CIRM's website (CIRM, undated).
A successful phase II trial would be followed by a phase III study, then a marketing application to FDA, Capricor added: “The end result could be an affordable stem cell therapy effective as part of a treatment regimen after a heart attack.”
At the 55th Annual Meeting and Exposition of the American Society of Hematology (ASH), held Dec. 7–10 in New Orleans, several presentations detailed advancements in genetically engineered cell therapies that showed early efficacy and safety in patients with blood disorders for whom standard treatments have been unsuccessful. Several studies presented during the meeting detail results using one method known as chimeric antigen receptor (CAR) cell engineering.
Two of the first three chronic lymphocytic leukemia (CLL) patients who participated in the study, which started in the summer of 2010, remain in remission, with tests revealing reprogrammed cells still circulating in their bodies, on guard to combat tumor cells that may reappear in the future.
Other highlights of the new research results include an 89% complete response rate among adult and pediatric patients with acute lymphoblastic leukemia (ALL).
Two key findings were presented in a single study (Grupp et al., 2013): • 19 of 22 pediatric patients with ALL (86%) experienced complete remission. The first patient treated with the protocol, who is now 8 years old, remains in remission 20 months later. Five patients have relapsed, including one whose tests revealed new tumor cells that do not express the protein targeted by the reprogrammed cells. • All five of the first adult ALL patients treated thus far experienced complete remission, the longest of which continues 6 months after treatment. One patient subsequently underwent a bone marrow transplant and remains in remission. One patient relapsed after 3 months with disease that also tested negative for the CD19 protein.
In two additional studies, 15 of 32 adult patients with CLL (47%) responded to the CTL019 therapy, with 7 of those experiencing a complete remission of their disease. These results are derived from a completed pilot study of 14 CLL patients (Porter et al., 2013a) and results to date of the first 18 patients in a phase II dose optimization (Porter et al., 2013b).
A team from
The team—whose presenting author was Marco L. Davila, MD, PhD—concluded that the results strongly supported integration of CAR T cell therapy in the modern paradigm for B-cell ALL therapy (B-ALL), by facilitating access to allogeneic-stem cell transplantation (SCT) for patients with relapsed B-ALL. Of 13 patients treated, four underwent allogeneic-stem cell transplantation (allo-SCT) and 5 were being prepared for allo-SCT. Of the remaining four patients, one was a non-responder, one was relapsed and not eligible for allo-SCT; one is in CR2 and medically ineligible for allo-SCT, and one had not been evaluated for treatment response.
In addition, the
James N. Kochenderfer, MD, of NCI's Experimental Transplantation and Immunology Branch and colleagues observed CAR expression in a mean of 70.5% of the T cells after developing a CAR encoded by a gammaretrovirus and incorporating variable regions of an anti-CD19 antibody, CD28 and CD3-zeta.
The researchers evaluated the anti-CD19 CAR T cells in 15 patients—9 of which had aggressive large cell lymphomas, and the rest had indolent B-cell malignancies. All patients received cyclophosphamide plus 25 mg/m2 fludarabine followed by 2.5×106 anti-CD19 CAR T cells/kg. Of the 13 patients evaluated for response, 7 achieved a complete remission, 5 achieved partial remission, and 1 patient achieved stable disease.
“We are particularly encouraged by the partial and complete responses that we observed in a number of patients with diffuse large B-cell lymphomas who had exhausted all other treatment options. This approach is still an early-stage experimental therapy, and we will continue to research to further improve the protocol and evaluate its value in additional patients with treatment-resistant disease,” Kochenderfer said (American Society of Hematology, 2013).
A year before cancer immunotherapy was named 2013 Breakthrough of the Year by the journal Science, a research team found success using the immune system to battle another deadly disease. In an article published in Nature, the team found that harnessing proteins from the human immune system can stop HIV/AIDS in mice and should be studied in humans as a possible treatment (Klein et al., 2012).
Florian Klein and colleagues in Michel Nussenzweig's Laboratory of Molecular Immunology at Rockefeller found that a combination of five different antibodies effectively suppressed HIV-1 replication and kept the virus at bay for 60 days after therapy was terminated, thanks to their longer half-life compared to current antiretroviral drugs, which require daily intake.
Such broadly neutralizing antibodies were identified and cloned from HIV-infected patients whose immune systems showed an unusually high ability to neutralize HIV. The antibodies were found to prevent HIV from infecting nonhuman primates, demonstrating the possibility for a vaccine in humans, but were thought to have little or no effect on established infections. The antibodies targeted gp160, a protein on the surface of HIV-1. While one antibody and even three alone could not stop the virus, five of them proved too much for gp160.
Previous antibody therapy experiments in humanized mice and in humans concluded that treatment with combinations of antibodies had only limited effects against established HIV-1 infection. That finding was based on experiments using broadly neutralizing antibodies that were orders of magnitude less potent than those in the 2012 study.
“Although HIV-1 infection in humanized mice differs in many important aspects from infection in humans, the results are encouraging to investigate these antibodies in clinical trials. It also may be that a combination of antibodies and the already established antiretroviral therapy is more efficacious than either alone,” Klein said, adding: “If this could be used as a treatment one day, it is conceivable that patients would only need to take traditional drugs until the virus is controlled, and then receive antibodies every two to three months to maintain that control. We're eager to explore if a benefit in HIV-1- treatment can be achieved in humans.” (Rockefeller University, 2012).