In a report on what is believed to be the first small clinical trial of its kind, researchers at the Johns Hopkins Kimmel Cancer Center say they have safely used immune cells grown from patients’ own bone marrow to treat multiple myeloma, a cancer of white blood cells.
Results of the trial involving a particular type of tumor-targeting T cell, known as marrow-infiltrating lymphocytes (MILs), are described in the May 20 issue of Science Translational Medicine.
“What we learned in this small trial is that large numbers of activated MILs can selectively target and kill myeloma cells,” says Johns Hopkins immunologist Ivan Borrello, M.D., who led the clinical trial.
MILs, he explains, are the foot soldiers of the immune system and attack foreign cells, such as bacteria or viruses. But in their normal state, they are inactive and too few in number to have a measurable effect on cancer.
Previous laboratory research by Borrello and his colleagues showed that activated MILs could selectively target and kill myeloma cells taken from patients and grown in laboratory culture flasks.
For the clinical trial, the Johns Hopkins team enrolled 25 patients with newly diagnosed or relapsed multiple myeloma, although three of the patients relapsed before they could receive the MILs therapy.
The scientists retrieved MILs from each patient’s bone marrow, grew them in the laboratory to expand their numbers, activated them with microscopic beads coated with immune activating antibodies and intravenously injected each of the 22 patients with their own cells. Three days before the injections of expanded MILs, patients received high doses of chemotherapy and a stem cell transplant, standard treatments for multiple myeloma.
One year after receiving the MILs therapy, 13 of the 22 patients had at least a partial response to the therapy, meaning that their cancers had shrunk by at least 50 percent.
Seven patients experienced at least a 90 percent reduction in tumor cell volume and lived, on average, 25.1 months without cancer progression. The remaining 15 patients had an average of 11.8 progression-free months following MILs therapy. None of the participants had serious side effects from the MILs therapy. The overall survival was 31.5 months for those with less than 90 percent disease reduction, but this number has not yet been reached in those with better responses. The average follow-up time is currently more than six years.
Borrello notes that several U.S. cancer centers have conducted similar experimental treatments, known as adoptive T cell therapy, but says the Johns Hopkins team is believed to be the only one to use MILs. Other types of tumor-infiltrating cells can be used, but they are usually less plentiful in patients’ tumors and may not grow as well outside the body, says Borrello.
In nonblood-based tumors, such as melanoma, only about one-half of patients have T cells in their tumors that can be harvested, and only about one-half of those harvested cells can be grown. “Typically, immune cells from solid tumors, called tumor-infiltrating lymphocytes, can be harvested and grown in only about 25 percent of patients who could potentially be eligible for the therapy. But in our clinical trial, we were able to harvest and grow MILs from all 22 patients,” says Kimberly Noonan, Ph.D., a research associate at the Johns Hopkins University School of Medicine.
Noonan says the small trial helped her and her colleagues learn more about which patients may benefit from MILs therapy. For example, they were able to determine how many of the MILs grown in the lab were specifically targeted to the patient’s tumor and whether they continued to target the tumor after being infused.
Additionally, the scientists found that patients whose bone marrow before treatment contained a high number of certain immune cells, known as central memory cells, also had better response to MILs therapy. Patients who began treatment with signs of an overactive immune response did not respond as well.
Noonan says the research team has used these data to guide two other ongoing MILs clinical trials. Those studies, she says, are trying to extend anti-tumor response and tumor specificity by combining the MILs transplant with a Johns Hopkins-developed cancer vaccine called GVAX and the myeloma drug lenalidomide, which stimulates T cell responses.
The researchers say the trials also have shed light on new ways to grow the MILs. “In most of these trials, you see that the more cells you get, the better response you get in patients. Learning how to improve cell growth may therefore improve the therapy,” says Noonan.
Kimmel Cancer Center scientists are also developing MILs to treat solid tumors such as lung, esophageal and gastric cancers, as well as the pediatric cancers neuroblastoma and Ewing’s sarcoma.
Experts report there are more than 20,000 new cases of multiple myeloma and more than 10,000 deaths each year in United States. It is the second most common cancer originating in the blood.
Other Johns Hopkins scientists who contributed to the research include Carol Ann Huff, Janice Davis, M. Victor Lemas, Susan Fiorino, Jeffrey Bitzan, Anna Ferguson, Amy Emerling, Leo Luznik, William Matsui, Jonathan Powell, Ephraim Fuchs, Gary L. Rosner, C. Epstein, Lakshmi Rudraraju, Richard F. Ambinder, Richard J. Jones and Drew Pardoll.
Funding for the study was provided by the Commonwealth Fund (5P01 CA015396, P30 CA006973) and the Baca and Morisi Funds.
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This is a report of a phase I clinical trial testing whether specific immune cells harvested from the bone marrow, grown in the lab and then re-infused into multiple myeloma patients can effectively change the immune environment in the patient and suggest a possibly improved disease outcome. It looks at using a different population of immune cells — marrow-infiltrating lymphocytes (MILs) — from those used in previous studies. These are both easier to retrieve and easier to grow in the lab, two factors that reduce the complexity of this treatment approach.
The release is in many ways a model for other organizations reporting on similar studies. The description of the study is clear, the language used appropriately conservative, and there is context regarding the novelty of the approach and current alternative treatments. Some discussion of possible costs — preliminary though it would have to be — would have completed the picture for readers. Rather than hyping such a study in a frenzied attempt to attract clicks and eyeballs, Hopkins presents the findings in a thoughtful way that reflects well on the institution’s reputation and will help build that reputation over the long haul.
Multiple myeloma is one of several cancers of the blood and the National Cancer Institute estimates that nearly 27,000 new cases of myeloma will be diagnosed this year. Less than half of patients live as much as five years after their diagnosis, and more than 11,000 patients are expected to die from the disease this year. Any new approach to treating this and other blood cancers stands to benefit the nearly 90,000 patients now living with this disease in the U.S.
The release, while loaded with information about the research, fails to mention costs related to this new approach at any point. This is in spite of the fact that the paper provides what’s necessary to fulfill this criterion. The study authors wrote: “The easy access to the tumor site, the absence of the need for surgical removal of the tissue containing the T cells, the numbers of cells obtained with the harvest, and the ability to expand products in all patients with a relatively short process at a reasonable cost contrast sharply with several limitations of TIL ACT” (a current therapeutic approach to the disease).
The release does a good job of spelling out the results of this phase 1 trial by providing data showing that MILs can target and kill cancer cells. It shows that in more than half of the study’s patients, their cancers had shrunk by at least half. In 15 of the 22 patients, their cancers did not progress for nearly a year after the MILs therapy. This wasn’t a controlled study, so it’s unclear how these patients would have fared without the MILs treatment, and the release could have attempted to provide some insight on that point. But we’re pleased that the release focuses appropriately on the apparent safety of the approach, rather than trying to make claims about survival benefits that aren’t supportable by this kind of small, uncontrolled study. The release also explains that the research provides information suggesting which patients might benefit best from this approach, and that other research at this cancer center is centered on testing this approach on different forms of cancer.
We’ll give this criterion a satisfactory rating since the release specifically spells out, “None of the participants had serious side effects from the MILs therapy.” However, the study is really too small, and the time span too short, to comment substantively on the possible harms that might be seen if and when the treatment is more widely used. The research paper actually makes the point that the new procedure doesn’t require the “surgical removal of tissue,” and the procedure can be done at bedside rather than an operating suite. But the removal of cells from the bone marrow is still an invasive procedure that carries its own risk of infection or other problems. The release would have benefited from at least mentioning this aspect.
The release makes a very good effort to objectively describe a technically complicated trial. It defines the trial at least twice as being “small” and calls it a “pilot,” suggesting that caution is appropriate when considering the results. It effectively explains the process involved in the treatments, including what was learned regarding the growth of cells in the lab after harvesting. It also points to the fact that while tumor-infiltrating lymphocytes (TILs) can only be retrieved from a quarter of the patient candidates for this technique, MILs were obtained from all of the patients in this study, suggesting that they may be a better tool for this therapy.
Describing multiple myeloma as “the second most common cancer originating in the blood” doesn’t add much to our understanding of this disease. However, other statistics provide context regarding the scope of the problem in the United States. We’ll give it a pass.
The funding sources for this research are listed in an end note in the release. No conflict of interest information is provided in the release, although the research paper discloses no conflicts.
The release does mention that other forms of this adoptive T cell therapy use different cells, suggesting that other approaches are possible. The release also notes, “Three days before the injections of expanded MILs, patients received high doses of chemotherapy and a stem cell transplant, standard treatments for multiple myeloma.”
The release points out that “several U.S. cancer centers have conducted similar experimental treatments” but adds that Johns Hopkins is the only one using the MIL cells. It also points to several other ongoing clinical trials at Hopkins that build on the findings of this small study. Using the terms “pilot” and “experimental,” the release signals that availability is very limited.
We like the fact that the headline itself defines this as a “pilot” clinical trial and that the lede says that it is “what is believed to be the first small clinical trial of its kind.” Those kinds of qualifiers both declare the specifics of the research and also provide informative caveats, allowing the reader to gauge how much credence to give to the findings. All too many other medical releases fail to provide this measured approach.
This release is conservative throughout in its choice of language in describing this research which, based on its findings, might be ripe for exaggeration.