There was an im­por­tant multiple myeloma-related presentation this Monday at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago.

The presentation summarized early results of a pilot clin­i­cal trial being conducted at the University of Pennsylvania. The trial, which is scheduled to enroll 10 re­lapsed myeloma patients, is testing a promising ap­proach to cancer treat­ment known as “chimeric an­ti­gen re­cep­tor” (CAR) T-cell ther­apy.

CAR T-cell ther­apy has generated impressive results when used to treat certain kinds of leukemia and lym­phoma. These results have led to a concerted effort to use CAR T-cell ther­apy to treat a range of dif­fer­en­t cancers, in­­clud­ing multiple myeloma.

Thus far, how­ever, the few attempts to use CAR T-cell ther­apy in multiple myeloma have shown limited suc­cess.

That is why there was such interest on Monday in the presentation at the ASCO meeting by Penn researcher Dr. Alfred Garfall. During the past five years, Penn’s CAR T-cell ther­apy – known as CTL019 (tisagen­lec­leucel-T) – has resulted in a number of headline-grabbing treat­ment out­comes in cancers other than multiple myeloma.

In addi­tion, a presentation by another Penn researcher at last year’s American Society of Hematology (ASH) meeting hinted at the possibility that CTL019 might be having some success in treating myeloma – despite the fact that CTL019 was not designed with multiple myeloma as its pri­mary disease target.

Although the results summarized during Dr. Garfall’s presentation may not be the home run many had hoped for, the presentation did not disappoint.

During his talk, Dr. Garfall reviewed results for the first five patients treated in the Penn trial. He reported that four of the first five patients responded to treat­ment. Three of the five con­tinue to main­tain disease control, and one of the patients achieved – and has sustained – a stringent com­plete response with no sign of min­i­mal residual disease. (Results for all five patients are summarized in Table 1, which is at the end of this article.)

These initial results of the Penn trial were achieved in patients who in many cases had been treated with – and stopped responding to – a number of other myeloma ther­a­pies. In addi­tion, patients could only par­tic­i­pate in the study if they had pre­vi­ously undergone a stem cell trans­plant and their disease progressed within a year of the trans­plant.

The patient who achieved a stringent com­plete response during the trial, for example, had pre­vi­ously been treated with 10 dif­fer­en­t myeloma ther­a­pies, and had progressed just six months after their first trans­plant.

“These results rep­re­sent an excellent proof of prin­ci­pal that we can engi­neer and grow T cells to effectively control multiple myeloma in patients with high-risk and highly aggressive disease,” Dr. Kenneth Shain, a myeloma specialist at the H. Lee Moffitt Cancer Center in Tampa, Florida, told The Beacon. CAR T-cell ther­apy is “a truly novel leap forward in the treat­ment of multiple myeloma and other types of cancer.”  Dr. Shain was not involved in the Penn study.

Both Dr. Shain and Dr. Prashant Kapoor, a myeloma specialist at the Mayo Clinic in Rochester, Minnesota who likewise was not involved in the Penn study, noted that results presented on Monday also show that CTL019 appears to be safe when used to treat multiple myeloma. Some patients with other blood cancers who were treated with the CTL019 ex­peri­enced life-threatening side effects, but this has not occurred thus far in the CTL019 myeloma trial.

Some Caveats

There are, how­ever, im­por­tant caveats about the initial CTL019 results that are worth bearing in mind.

First and foremost, the data Dr. Garfall presented on Monday are for just five patients, and the follow-up with these patients has been short. Thus, the longer-term out­comes of CTL019 treat­ment are not yet known.  This is particularly noteworthy because some results Dr. Garfall shared during his presentation suggest that CTL019 may not have as durable a response in multiple myeloma as has been seen in other blood cancers (see later in this article for more details on this issue).

Second, the ongoing Penn trial is not testing CTL019 ther­apy by itself. All patients in the trial first underwent a stem cell trans­plant as part of the trial and were then admin­istered a single infusion of CTL019 after their trans­plant. Thus, the treat­ment responses tabulated in Table 1 below are responses to the com­bi­na­tion of stem cell trans­plan­ta­tion and CTL019 ther­apy – not just CTL019.

“The pre­lim­i­nary results presented on Monday make it dif­fi­cult to tease apart the impact of the second autol­o­gous stem cell trans­plan­ta­tion versus CTL019 ther­apy,” explained the Mayo Clinic’s Dr. Kapoor.

When asked during an email interview with The Beacon what plans there are to test CTL019 further in mul­tiple myeloma, Dr. Garfall said that it is too early to tell. He and his colleagues would like longer-term data before making any final de­ci­sions about those plans. That said, he believes the avail­able data strongly sug­gest that treat­ment with CTL019 has been effective in at least some of the myeloma patients whose results he summarized during his ASCO presentation.

Background

Chimeric an­ti­gen re­cep­tor T-cell ther­apy belongs to a broader class of cancer ther­a­pies known as immu­no­therapies, which seek to use the body's immune system to fight cancer.  CAR T-cell ther­apy also belongs to a class of treat­ments known as adoptive cellular ther­a­pies, which focus on using altered T cells to treat dis­eases.

T cells are a type of white blood cell that attack and kill viruses and cancer cells. Cancers that are able to take hold in the body, how­ever, have developed ways of making it hard for T cells to suc­cess­fully attack them. One way they accomplish this is by making it dif­fi­cult for the T cells to recog­nize them as cancer cells.

In CAR T-cell ther­apy, a cancer patient’s T cells are harvested and then genetically altered so that they are better able to identify and attack the patient’s specific type of cancer, such as a multiple myeloma. The altered T cells are then stimulated to reproduce so that a large number of the altered cells can be re-infused back into the patient’s body to (hopefully) treat the patient’s cancer.

The way the T cells are altered to better identify and attack a specific cancer is by modifying them so that they are attracted to a protein found on the surface of the cancer cells. In the case of CTL019, for example, the T cells are altered so they are attracted to cells with a surface protein known as CD19. This protein is com­mon­ly found on white cells known as B cells, and CTL019 was initially tested – and found to be extremely suc­cessful – in patients with blood cancers involving B cells.

CD19 is not typically found, how­ever, on multiple myeloma cells. The Penn researchers thus initially tested CTL019 in other blood cancers that have CD19 on their cell surface. Before the Penn trial started, how­ever, researchers at the Baylor College of Medicine in Houston ini­ti­ated a small trial of a CD19-targeted CAR T-cell ther­apy in patients with lym­phoma, leukemia, and multiple myeloma.  They presented early results of their study at the 2014 Bone Marrow Transplantation Tandem meeting, reporting that the three re­lapsed myeloma patients in the study main­tained stable disease for 2, 11, and 17 months as a result of the treat­ment (meeting abstract 6, related slides [PDF] courtesy of Dr. Carlos A. Ramos).

In addi­tion, researchers in China are conducting a trial of CAR T-cell ther­apy in re­lapsed multiple myeloma patients. The Chinese ther­apy targets the protein CD138, which is commonly found on myeloma cells.  Initial results of this trial were recently published. They show that the first five patients treated with the CD138-targeted ther­apy achieved stable disease, but no partial responses or better were observed.

Neither the Chinese trial nor the Baylor study com­bined CAR T-cell ther­apy with stem cell trans­plan­ta­tion, as is being done in the Penn CTL019 study.

Investment Flows To CAR T-Cell Research

The sig­nif­i­cant success that CAR T-cell ther­apy has had in treating some cancers has led to a surge of in­vest­ment flowing into CAR T-cell research. Large pharma­ceu­tical com­pa­nies have made sub­stan­tial invest­ments in smaller bio­tech com­pa­nies specialized in CAR T-cell ther­apy, and com­pa­nies large and small have signed lucrative licensing deals with major cancer treat­ment centers for access to their pro­pri­e­tary CAR T-cell tech­nolo­gies.

This surge in industry funding is flowing to myeloma-related CAR T-cell research just as it is to research in­volving other cancers. Important licensing deals concluded over the past several years that will either directly, or indirectly, provide industry sup­port for CAR T-cell research related to multiple myeloma in­clude:

• The Swiss pharmaceutical company Novartis’s licensing of the rights to CTL019 from Penn
• Celgene’s partnership with the biotech company Bluebird Bio to develop a CAR T-cell therapy for multiple myeloma, and the two companies jointly collaborating with Baylor in its CAR T-cell program
• Ohio State’s licensing of its CAR T-cell technologies, including one for multiple myeloma targeting the protein CS1, to the French biotech company Cellectis – which, in turn, has a collaboration with Pfizer
• MD Anderson’s licensing of its CAR T-cell technology to the biotech companies Intrexon and Ziopharm in return for payments over the next three years valued at more than $100 million dollars.

Industry’s optimism about CAR T-cell ther­apy also has spilled over to related ther­a­pies, in­­clud­ing ones aimed at multiple myeloma.  For example, Sloan-Kettering last fall announced that it had licensed rights to several adoptive cellular ther­a­pies – in­­clud­ing a T-cell ther­apy for multiple myeloma that targets the protein WT1 – to the bio­tech com­pany Atara Biotherapeutics.

Design & Initial Results Of The Penn CTL019 Study

The Penn trial of CTL019 was designed to be a pilot study of the ther­apy in multiple myeloma. The trial was open to myeloma patients who had undergone one pre­vi­ous stem cell trans­plant and ex­peri­enced disease pro­gres­sion within a year of the trans­plant.

Patients did not have to have any specific genetic or disease markers to par­tic­i­pate in the study.  It was not nec­es­sary, for example, that patients have myeloma cells with more CD19 on their surface than is typically seen in myeloma patients.

During the trial, each patient underwent a stem cell trans­plant after receiving high-dose mel­phalan.  Then, 12 to 14 days post trans­plant, they received an infusion of the CTL019 ther­apy.  The infusion consisted of altered T cells produced from cells harvested from the patient prior to their trans­plant during the trial.

Preliminary trial results for five patients were presented at the ASCO session on Monday.  Another two patients have started the trial since the researchers prepared their presentation, and three other patients are scheduled for treat­ment in the near future.

Efficacy And Safety

Four of the five patients responded to the com­bi­na­tion of the trans­plant and CTL019 ther­apy, and two of those four patients had post-transplant responses that lasted longer than they achieved after their first trans­plants.

One of the patients achieved a stringent com­plete response and was found to be “minimal residual disease negative” (MRD-), meaning no myeloma cells could be found in the patient’s bone marrow using sensitive detection methods.  This patient’s response to the com­bined ther­apy has lasted almost a year.

No sig­nif­i­cant toxicity attributable to CTL019 has been seen thus far during the trial. Four of the first five patients ex­peri­enced transient hypogammaglobulinemia, or low gamma globulin levels.  One patient ex­peri­enced mild cytokine release syn­drome, a con­di­tion where inflammation and symp­toms of in­fec­tion occur without any infectious cause.  Severe cases of cytokine release syn­drome have occurred in the past as a result of CAR T-cell ther­apy.

Source Of CTL019’s Potential Anti-Myeloma Effect

Dr. Garfall stated during his presentation that he and his colleagues do not yet know how CTL019 has had the anti-myeloma effect they believe it has had in some of the trial patients. As mentioned earlier, the CD19 protein that is targeted by CTL019 is not found to any great extent on most myeloma cells. In fact, tests done on the myeloma cells of the patient who achieved a stringent com­plete response during the trial showed that 99.95 per­cent of those cells did not have any CD19.

One hypothesis is that CD19 may be on cells that have been described by some researchers as “myeloma stem cells.” These cells are hypothesized to be the original – and ongoing – source of myeloma cells in myeloma patients. If such myeloma stem cells exist, and if they have CD19 on their surface, then this could explain the poten­tial anti-myeloma effect of CTL019.

Another hypothesis is that CD19 may be on cells that play an im­por­tant role in nurturing and sustaining myeloma cells. By killing off those cells, CTL019 may indirectly be having an anti-myeloma effect.

Limited Persistence Of The Altered T Cells

One of the disappointing results of the Penn trial thus far concerns the persistence of the altered T cells that were infused into patients during the study.

In pre­vi­ous trials of CTL019 in other blood cancers, the altered T cells often persisted in patients for long periods of time. This, in fact, is one of the attractive aspects of CAR T-cell ther­apy. The single infusion of altered T cells can have a long-term effect on the patient’s cancer because the altered cells are able to reproduce and pass on their anti-cancer capabilities to their progeny.

This did not happen during the CTL019 trial. The altered T cells did engraft in all five patients, but they did not persist for an extended time.

In his interview with The Beacon, Dr. Garfall said he and his colleagues are not certain why this happened, although they have several theories. One option he said that is being con­sidered to address the issue of persistence is to give myeloma patients more than just one infusion of altered T cells.

For more in­­for­ma­tion, please see abstract 8517 at the ASCO meeting website.

Table 1
Individual Patient Data & Preliminary Outcomes Data
Penn CTL019 Relapsed Multiple Myeloma Clinical Trial (ASCO 2015)