news in this section Celgene wagers on Sutro’s cell-free platform to ramp up ADCs p1175

Listeria vaccines join the checkpoint frenzy p1176

Once-yearly device takes on daily and weekly diabetes drugs p1178

Listeria vaccine Cell surface TLRs

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Endosomal TLRs CD8

Cytosolic PR receptors

Listeria secreted PAMP Endosomal degraded Ag Listeria secreted Ag

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The most advanced clinical results using antiCD19 chimeric antigen receptor (CAR) T cells, published in October, have shown unprecedented remissions in patients with relapsed or refractory acute lymphoblastic leukemia (ALL). Two phase 1/2a trials published in the New England Journal of Medicine (N. Engl. J. Med. 371, 1507–1517, 2014) conducted by the University of Pennsylvania’s Perelman School of Medicine (Penn) and Basel-based Novartis, involving T-cell therapy CTL019, showed that 27 out of 30 patients with relapsed or refractory ALL experienced complete remissions, with some lasting up to 2 years. Another phase 1 study using Santa Monica, California–based Kite Pharma’s KTE-C19, conducted by the Pediatric Oncology Branch of the National Cancer Institute and published in The Lancet (doi:10.1016/S0140-6736(14)61403-3, 10 October 2014), found that 14 of 20 patients experienced a complete response. But glimpses of striking success in difficult-to-treat cancers have often been accompanied by toxic bursts of cytokines, which can be fatal. Companies are developing a variety of low- and high-tech strategies to mitigate the effects of massive cytokine release—from a molecular ‘dimmer switch’ to better hospital protocols for anticipating the likelihood of severe toxicity. Among the burgeoning success of immunotherapies, adoptive T-cell therapies have stood out. Since Novartis licensed rights to the University of Pennsylvania’s CAR-T programs and agreed to help fund the university’s Center for Advanced Cellular Therapeutics in August 2012, and data from Penn’s and others’ anti-CD19 programs emerged in B-cell malignancies, the field has racked up hundreds of millions of dollars in investment. Seattle-based Juno Therapeutics, before going public on 17 November, had already accrued $176 million in a series A and $134 million in a series B round. Kite Pharma in an initial public offering in June 2014 raised $127.5 million (as of Nov. 7 the company was valued at a whopping $1.75 billion by investors). All of this despite the challenges posed by cytokine storm, known clinically as cytokine release syndrome (CRS). “People are coming to realize that T cells can be potent and effective but also quite

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Developers seek to finetune toxicity of T-cell therapies

T cells fighting tumors can whip up a storm of cytokines; researchers are seeking ways to keep the storm under control.

dangerous, and the need for safety is implicit in this approach,” says Tom Farrell, CEO of Bellicum Pharmaceuticals, a Houston-based company that filed for IPO on 18 November. CRS develops when the infused T cells proliferate as they attack a tumor, releasing a massive quantity of inflammatory cytokines. Depending on the tumor burden, the cytokine release, whose main actors include interferon-g and interleukin-6, can cause severe symptoms that can be life threatening. In March, the US Food and Drug Administration placed a trial testing Juno’s anti-CD19 therapy at the Memorial Sloan Kettering Cancer Center in New York on temporary hold after two patient deaths. The regulators lifted the hold in August after the investigators amended the trial protocols. To deal with adverse reactions, companies are developing a range of approaches. Most practical, perhaps, are grading schemes to predict CRS—based on factors like tumor size or patient comorbidities—developed by teams led by Crystal Mackall, chief of pediatric oncology at the National Cancer Institute, and by Carl June and Stephan Grupp from Penn.

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MSKCC has also refined patient segmentation and placed higher hurdles for study eligibility—preventing, for instance, patients with a history of heart problems from taking part (Nat. Biotechnol. 32, 604, 2014). CRS is a transient event that subsides roughly 1 week to 10 days after the cells are infused, says David Chang, EVP of R&D and chief medical officer of Kite Pharma, and it is mostly treatable with standard patient management. Now that CRS is a recognized side effect, “physicians will be able to manage it much better,” says Chang. The cytokine storm is a “mechanistic side effect that occurs during expansion of infused cells and tends to correlate with efficacy” of the treatment, he says. Should CRS develop, the bluntest tool at clinicians’ disposal is a general dampening of the immune system through administration of steroids (a common strategy for managing runaway T-cell toxicity in organ or bone marrow transplant), though this sledgehammer approach also abruptly halts any tumorfighting T-cell efficacy. Physicians have also begun using the anti–interleukin-6 receptor antibody Actemra (tocilizumab) to counteract 1171

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NEWS one of the storm’s main cytokines. For example, in a study of Novartis/Penn’s CTL019 to be presented at the American Society of Hematology meeting in early December, 3 of 30 patients with relapsed or refractory chronic lymphocytic leukemia were treated with Actemra to blunt high-grade CRS; all three recovered from CRS, and of those, two responded to the therapy. Actemra, sold by Roche to treat rheumatoid arthritis, does not seem to halt the efficacy of CTL019, but not all clinicians are satisfied that it meaningfully alters the course of CRS. Looking ahead, the Penn researchers and others are trying to develop more potent CAR T cells that could elude the risk of CRS altogether. At Penn, for example, June’s team found that CAR T cells containing inducible co-stimulator I (ICOS), when transferred into mice, generate interleukin-17–producing effector cells with highly efficient antitumor responses (Blood 124, 1070–1080, 2014). With fewer T cells needed to produce complete remissions, the likelihood of a cytokine storm from excessive proliferation diminishes. Introducing an ‘off switch’ into the engineered T cells is a more sophisticated approach. The CaspaCIDe system from Bellicum, a self-destruct switch triggered by a small molecule, was originally developed by Ariad Pharmaceuticals. Bellicum, founded in 2004, engineers its T cells with this system, introducing a binding domain for a small molecule drug and the signaling domain of caspase-9, a protein in an apoptosis pathway. Infusion of the small molecule, AP1903, causes the binding domains of CaspaCIDe to dimerize, bringing together the caspase-9 domains, which then activate caspase-3 and lead to programmed cell death. The company has raised more than $100 million, including an August 2014 series C that brought in $55 million from a long list of investors. The company’s lead program has been proven successful in the clinic in quelling graft-versus-host disease following bone marrow transplant (N. Engl. J. Med. 365, 1673–1683, 2011). “We designed CaspaCIDe to serve as a brake that you can apply only as necessary,” says Farrell. In Bellicum’s collaborators’ experience with the technology in graft-versus-host disease, the majority of cells are eliminated in roughly 30 minutes. The

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first CAR-T study incorporating CaspaCIDe is being conducted by the US National Cancer Institute and is in a phase 1 dose-escalation study in pediatric patients with osteosarcoma or other non-neuroblastoma, GD2-expressing solid tumors. Another new technology, from Cambridge, Massachusetts–based startup Unum Therapeutics, tunes the T-cell response up or down by co-infusing different doses of a targeting antibody with the engineered T cells. Unum raised $12 million in series A financing in October from Atlas Venture, Fidelity Biosciences and Sanofi-Genzyme BioVentures to advance its antibody-coupled T-cell receptor (TCR) platform, which creates T cells that use therapeutic antibodies, such as antiCD20 Rituxan (rituximab), to direct an antitumor attack and is based on the work of Dario Campana at the National University of Singapore. The technology has parallels to the CAR technology but takes advantage of industry’s decades-long efforts to fine-tune antibody therapeutics themselves. It also leverages the binding properties of a CD16 receptor, which Unum installs on the membranes of T cells to bind to any tumor-targeting antibody.  “It uses well-known signaling components for T-cell receptor and co-stimulatory pathways, which allow us to get proliferation and persistence out of the T cells,” says Unum CSO Seth Ettenberg, formerly the Novartis Oncology Biologics site head in Cambridge, Massachusetts. But “it is fundamentally different from the CAR approach because we’ve decoupled the targeting domain from those domains that drive the T cell.” When a targeting antibody—against CD20, GD2 or whatever antigen Unum goes after—is administered, T-cell activity ramps up. If that antibody is dialed down or no longer present, the activity of the antibody-coupled TCR is reduced or eliminated. Different concentrations of the targeting antibody should therefore lead to different levels of T-cell activity. “We have the first dimmer switch for a chimeric T-cell receptor,” says Ettenberg. The company’s first clinical trial— a phase 1 dose-escalation study—in patients with persistent B-cell malignancies who are also receiving Rituxan—is slated to commence in December at the National University of Singapore and Singapore General Hospital. Although CAR-T therapies can be engineered to recognize antigens on the cell sur-

face, a related technology, T-cell therapy with engineered TCRs, can target antigens that are not expressed on tumor cell membranes. Several players in the CAR-T field, including Juno and Kite, are pursuing TCR therapies. The UK startup Adaptimmune, located in Oxford, which announced a $104-million series A financing in September, has staked out a leading position. The company’s technology enhances the natural TCR affinity to cancer epitopes, normally very low, to overcome tolerance to cancer. Besides the ability to target intracellular antigens, “using a TCR you’re using a natural signaling mechanism of the cell and the natural co-stimulatory mechanisms,” claims Gwendolyn Binder-Scholl, Adaptimmune EVP and head of clinical and regulatory development. “So we get a natural expansion and contraction of the immune system, which is why CRS and other toxicities may be milder with the Adaptimmune approach than with CD19 CAR-T therapy,” she says. “We’re seeing the occasional case of CRS,” says Adaptimmune medical director Tom Holdich, including two patients diagnosed with mild CRS in its ten-patient pilot trial of NY-ESOc259T, a TCR synovial sarcoma therapy being co-developed under a strategic cancer immunotherapy partnership with London-based GlaxoSmithKline. “But the severity of the type of reactions we’ve had to date has not required active treatment.” In all, Adaptimmune has five studies ongoing: two in myeloma, one in sarcoma, one in melanoma and one in ovarian cancer. As physicians at the major academic centers where T-cell therapy trials are taking place come to grips with managing CRS, the focus can return to the unusually strong efficacy demonstrated by these early stage therapies. James Yang, senior investigator at the National Cancer Institute says that in most cases, CRS can be treated by reducing fever and replenishing lost fluids. “It’s the rare patient that goes on to major organ dysfunction, but even in those cases if you support them,” the storm will pass. “For some cancers, immunotherapy is the only curative option,” and avoiding all toxicity associated with those therapies is not necessarily the best thing for patients. “There are very few things more toxic than uncontrolled metastatic cancer,” he says. Chris Morrison Yardley, Pennsylvania

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