After the 2017 approvals of Kymriah (tisagenlecleucel, CTL-019, Novartis AG) and Yescarta (axicabtagene ciloleucel, Gilead Sciences Inc., Kite Pharma Inc.), the American Society of Clinical Oncology named chimeric antigen receptor (CAR) T cell immunotherapy the clinical cancer advance of the year, and said that CAR T cells are "poised to transform" the treatment of pediatric acute lymphoblastic leukemia (ALL).

For those patients, of course, that transformation means everything. But their number is extremely small.

The relapsed pediatric ALL population, Novartis AG's Global Cell & Gene Therapies Business Leader Samuele Butera said at the BIO CEO meeting in New York last week, is a few hundred patients globally.

Relapsed diffuse B-cell lymphoma (DLBCL), which is one of the indications Yescarta is approved for, and the next indication Novartis is pursuing for Kymriah, affects about 6,000 patients annually in the U.S.

At BIO CEO, Butera stressed the bright side of starting a new class of therapy in a small patient group, saying it had allowed Novartis to work on "clinical, manufacturing, and commercialization [innovation] in a tightly integrated fashion."

But "the major challenge confronting cancer immunotherapy today," Steven Rosenberg told the audience at a recent talk at the National Institutes of Health, "is the development of effective immunotherapies for [the] 80 percent of patients with metastatic epithelial solid cancers."

Solidifying CAR success

For cell-based therapies to be successful in solid tumors it will take interlocking advances in improving efficacy and managing potential toxicity. And once those are overcome, it will take manufacturing advances to produce enough cells to meet the demand.

Solid tumors are challenging in part because they largely lack unique antigens. And while a number of targeted therapies work on antigens that are overexpressed on tumor cells but also found on other cells, that strategy has proven trickier with CAR T cells.

Both Kymriah and Yescarta target CD19, which is not specific to tumors. It is, however, found only on B cells and plasma cells. And as long as they receive antibody infusions, patients can live quite well without those particular cell types.

So even though Kymriah and Yescarta are not specific to tumor cells, they are specific enough.

Solid tumor targeting, though, is a different ball game.

"If you target a normal component, then any cell that expresses that component will be destroyed," Rosenberg said. "We learned this lesson the very hard way by attempting to catch the window of HER2 expression on breast cancers and colon cancers."

The first patient treated at the NIH with HER2-targeting CAR T cells, who had metastatic colon cancer, "died very rapidly" – within days of cell administration – "because of destruction of their normal cells."

Other trials using different CAR T constructs to treat both sarcomas and glioblastoma have since managed to avoid severe toxicity. But the case is a stark reminder, Rosenberg said, that "one has to be very wary of the fact that [targets] may be expressed on normal cells that will also be destroyed."

Companies are attempting to increase the specificity of CAR T cells by engineering the cells to respond to more complex signals. Cell Design Labs Inc. (CDL), which was acquired by Gilead in December 2017, has developed the synthetic Notch (synnotch) technology. The technology enables engineering of cells that are responsive to a combination of signals chosen by the investigators.

At Gilead's most recent quarterly conference call, executive vice president of research & development and chief scientific officer Norbert Bischofberger highlighted synnotch technology as "a reason why we are excited about CDL."

A synnotch engineered cell, he added, "essentially needs two antigens for the cell to get activated, so it gives you a much better specificity [because] both have to be present at the same time on the same cell surface." Other possibilities include CAR T cells that target cells that express one antigen, but do not express another.

Another possibility is the anatomically restricted delivery of cells. New York-based Mustang Bio Inc. is pursuing several solid tumor indications with CAR T cells. In 2016, researchers from the City of Hope published a case study of a patient with recurrent multifocal glioblastoma who had a transient complete response to Mustang's MB-101, which targets interleukin-13 receptor alpha 2 (IL13R alpha 2) .

In the case report, which was published in the Dec. 29, 2016, issue of The New England Journal of Medicine, as well as in the ongoing phase I trial, the cells were delivered "locoregionally," directly into the cranium and the ventricles.

In terms of efficacy, too, solid tumors are more challenging than the B-cell tumors where CAR T cells have racked up their early successes.

The reason is the immunosuppressive microenvironment of solid tumors, which can shut down CAR T cells as they do regular T cells.

At the BIO CEO meeting, Adelene Perkins, CEO of Infinity Pharmaceuticals Inc., said that with cell-based immune therapies, "turning the immune system on is not enough – the key is making sure that it doesn't get shut off... many of the approaches now being developed are making sure that we can keep the immune system turned on."

One way to keep anti-tumor immunity going is through editing the cells to be unresponsive to shutdown signals. Several companies have licensed CRISPR gene editing technology to make different edits to their cells that they hope will further this goal.

Making CARs like Fords, not Lamborghinis

Both toxicity and efficacy issues affect the need for scalability of the technology that is necessary to manufacture CAR T cells.

At the BIO CEO meeting, an audience member mentioned that CAR T toxicity issues are such that in some hospitals, doctors are proactively reserving ICU beds.

Butera pointed out, though, that toxicity management at institutions such as the Children's Hospital of Philadelphia, where the technology was first developed and where many patients have been treated, toxicity management has "greatly improved" with experience, and precautionary ICU bed reservation is not necessary.

Sometimes, not even a hospital bed is necessary. In the phase III JULIET trial testing Kymriah in DLBCL, more than 25 percent of patients were treated in an outpatient setting, and the majority of those patients did not need to be hospitalized for at least three days after treatment, when the acute toxicities of CAR T cells tend to show up.

Outpatient care could be matched by point-of-care cell transduction; technologies for such transduction are being developed, for example, by Jennifer Adair's laboratory at the Fred Hutchinson Cancer Research Center, which is working on "gene therapy in a box" approaches that could allow the desktop transformation of T cells as well as blood stem cells.

Locoregional delivery also helps limiting not just toxicity, but the number of cells that have to be administered.

On the other hand, Mustang Bio CEO Manuel Litchman told BioWorld Insight, "when I think about solid tumors, I think about multiple administrations."

The MB-101 treated patient whose case report was published in NEJM received 16 administrations of cells – "luckily, they were all from a single apheresis," the procedure by which blood is removed and cells are isolated.

Litchman said he expects that multiple applications will remain standard for solid tumors, though he did note that "five years ago, people were saying that you couldn't achieve one and done in [B cell] cancers either."

"The early days of any technology are going to present manufacturing challenges," Litchman said. "But cell processing is becoming an easier hurdle to overcome... the landscape is very different from what it was when Novartis, where I was working at the time, licensed in the CAR technology from U Penn."