The papers describe a treatment in which engineered T cells fight leukemia, originally hailed as a “major advance” in the New York Times. Since the first paper appeared in 2011, co-author Carl June at the University of Pennsylvania has received more than $7 million in grants from the National Institutes of Health, according to MIT Technology Review. But according to a newly published correction, the three NEJM papers failed to note in the acknowledgement section that an important component of the experiments was supplied by researchers at St. Jude Children’s Research Hospital.
Three articles omitted an acknowledgment of work associated with the chimeric antigen receptor that was used in the studies. The acknowledgments at the end of each article should have included the following sentence: “Drs. Dario Campana and Chihaya Imai and others at St. Jude Children’s Research Hospital designed, developed, and provided under material transfer agreements the chimeric antigen receptor (CAR) that was used in this study.” The articles are correct at NEJM.org.
There’s a line in the correction that Porter submitted — which was forwarded to us by Susan Phillips, a Vice President at Penn Medicine — that is not in the final correction:
The authors regret not acknowledging the contributions of Drs. Campana and Imai and St. Jude Children’s Research Hospital in these articles.
Given that one paper is now five years old, we asked Phillips why Porter requested the corrections 11 months ago:
I am legally precluded from responding to this question.
All three papers included in the correction earned a “highly cited” distinction from Thomson Reuters Web of Science:
- Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia, published in 2011 and cited 873 times
- Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid Leukemia, published in 2013 and cited 542 times
- Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia, published in 2014 and cited 224 times. (According to Web of Science, “This hot paper was published in the past two years and received enough citations in September/October 2015 to place it in the top 0.1% of papers in its academic field.”)
MIT Technology Review explains how the 2011 paper boosted June’s career:
For Penn, the success uncorked a tidal wave of prizes and funding, including more than $7 million in NIH grants in June’s name since then. June rocketed to scientific stardom partly thanks to Emily Whitehead, a little girl cured by an infusion of T cells at Penn whose heartwarming case was described in scores of articles and the Ken Burns cancer documentary, The Emperor of All Maladies.
The paper that described Whitehead’s treatment, published in 2013, is among those now being corrected.
MIT Technology Review reached Campana for comment, who
said he was pleased with the results of Penn’s trials and those of other centers. “It’s been beneficial for immunotherapy,” he said. “But we developed this receptor. There is no question about that.”
The MIT Technology Review article also provides a nice description of how the therapy works, and how the dispute arose:
The basic idea of T-cell therapy is to remove a patient’s white blood cells and then add a molecule to the cells which can stick onto cancer cells, lock-and-key style. The cells are then returned to the patient. But early studies flopped when the cells proved inactive.
Scientists realized they needed to add an additional signal—a kind of molecular tail jutting into the cell—to stimulate them to divide and attack the tumor. Credit for that idea belongs to several scientists, including Helen Finney, then of Celltech Therapeutics in London, and Michel Sadelain at Memorial Sloan Kettering in New York.
By 2003, Campana, who now works at the University of Singapore, had created one such molecular design and agreed to share it with Penn, after June asked for a copy. As is typical, the two institutions signed a contract known as a “material transfer agreement.” While public attention is often on patent disputes, such material agreements are far more common in science, used whenever researchers want to share DNA, cells, or even whole animals.
The dispute arose when June’s papers appeared to take credit for the DNA design and didn’t mention St. Jude’s contribution, though both scientific protocol and the materials agreement called for recognition of it.
Phillips told us she could not elaborate on what the material transfer agreement said, as it was part of a lawsuit:
We cannot comment on the subject matter of the litigation, other than to say the case has been settled.
Phillips noted that source of the chimeric receptor design is acknowledged in a paper co-authored by June and Campana, “Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo,” published in Molecular Therapy in 2009. That paper, which all three of the NEJM papers cite, explains the origin of the receptor:
The cDNA for the CARs that contain a truncated form of the TCR-ζ intracellular domain (αCD19-Δζ), a full-length TCR-ζ domain (αCD19-ζ) or a TCR-ζ domain in cis with the intracellular domain of the 4-1BB receptor (αCD19-BB-ζ) were generated at St Jude’s Childrens Research Hospital. These complete CAR sequences were amplified directly from the provided plasmids by PCR.
(For our eagle-eyed readers, that 2009 paper added a correction last year.)
In an email to the MIT Technology Review that she forwarded to us, Phillips noted that the NEJM papers describe a:
complete cell therapy based on the June laboratory’s innovations in the field of cell expansion and transfection, and the chimeric antigen receptor is an interchangeable part that could not have succeeded on its own as a clinical therapy.
This story goes beyond a question of proper credit in three papers. A 2013 story in the Philadelphia Inquirer explains how what started as a collaboration devolved into a lawsuit:
That relationship started as a collaboration, both parties’ legal papers show. In 2003, Carl June heard Dario Campana, then a pediatric oncologist at St. Jude, describe a CAR T cell he had built with a relatively obscure booster signal, called 4-1BB, that no other researchers were using.
That led to an agreement between the two centers. It said June could do studies using Campana’s CAR and even file patents “claiming inventions through use” of it, but June could not commercialize any product with the Campana CAR without permission from St. Jude.
St. Jude filed suit in July 2012, shortly after Penn entered into a much-publicized partnership with pharmaceutical giant Novartis to develop the June team’s immunotherapy.
In April 2015, the Inquirer reported that the suit was settled in April 2015, with Novartis agreeing to pay
$12.25 million now – and more in the future – to Juno Therapeutics, a well-funded biotech start-up that is also working on therapies designed to harness the immune system to beat cancer.
Juno will share some of the payments with St. Jude Children’s Research Hospital, which launched the legal battle in 2012, claiming Penn effectively stole key technology that the esteemed Memphis hospital had invented.
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