immune-checkpoint inhibitors march on, now in combinations

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NATURE BIOTECHNOLOGY VOLUME 32 NUMBER 4 APRIL 2014 297 IN this section Cancer trial assesses clinical benefit of gene- targeted drugs p306 Fraunhofer to mine Sanofi microbial collection p305 Leptin therapy gets FDA green light p300 study suggests that inhibition of extracellular signal–regulated kinase (ERK) may overcome combined resistance to BRAF and MEK inhi- bition (Cancer Res. 4, 61–68, 2013). Another suggests that inhibiting autophagy, a cell sur- vival mechanism induced in response to stress, with the anti-malaria drug hydroxycholoro- quine can achieve a similar outcome (J. Clin. Invest. 124, 1406–1417, 2014). A third found that inhibition of PD-1 and another immune checkpoint, T-cell immunoglobulin-3 (Tim-3), could improve the immunogenicity of cancer vaccines, as both proteins, which function as inhibitory T-cell co-receptors, are upregulated following vaccine administration (Cancer Res. 74, 10451055, 2014). Although the hypotheses that are now being tested in the clinic are becoming richer, in terms of supporting data, not every good idea will get that far. “The challenge Immune-checkpoint inhibitors march on, now in combinations The pace of deal-making in cancer immuno- therapy has picked up sharply since the start of the year. In February, Merck, of Whitehouse Station, New Jersey, teamed up with Pfizer, Incyte and Amgen, to begin phase 1/2 trials of its programmed cell death 1 (PD-1) inhibi- tor MK-3475 in four different combinations, while entering a large-scale discovery and development alliance with nanobody devel- oper Ablynx of Ghent, Belgium (Table 1). Meanwhile, New York–based Pfizer and Johnson & Johnson, of New Brunswick, New Jersey, and MedImmune, the biologics arm of London-based AstraZeneca, are all tap- ping into the immunotherapy expertise of the University of Texas MD Anderson Cancer Center, in Houston, to deepen their under- standing of the underlying biology (Box 1). Although each of these initiatives is early stage and exploratory, taken together they demonstrate the potential big pharma sees in developing immune-checkpoint modulators for cancer combined with vaccines, chimeric antigen receptor technology, cytokine-neutral- izing antibodies and small-molecule drugs. Immunotherapy and targeted therapy have largely developed in parallel universes up to now. As they mature, the prospect of their convergence is becoming tangible. Big pharma companies are forging deals in the space, hop- ing to make up ground on New York–based Bristol-Myers Squibb (BMS), who developed the first approved checkpoint inhibitor, Yervoy (ipilimumab), a human monoclonal antibody targeting cytotoxic T-lymphocyte activator-4 for treating metastatic melanoma (Nat. Biotechnol. 29, 375, 2011). Despite the current fascination for combin- ing immunotherapies with different agents, the whole field remains at an early stage of devel- opment. Some trials have already delivered results, although most regimens have not yet been optimized. A combination of Zelboraf (vemurafenib), a BRAF inhibitor marketed by Basel-based Roche, and BMS’s Yervoy caused liver toxicity problems in melanoma patients, although these were reversible (N. Engl. J. Med. 368, 13651366, 2013). Pairing a targeted agent with one or more immune-checkpoint agents appears to offer complementary mechanisms of action. A kinase inhibitor can reduce the tumor load before an immune response has time to develop, and an activated immune system may then mop up residual cancer cells that have become resistant to the drug therapy. The effect could be particularly pronounced in melanoma, which has a very high mutation frequency. “Those mutations actually create opportunities for the immune system to recog- nize the cancer,” says Suzanne Topalian, direc- tor of the melanoma program at the Kimmel Cancer Center at Johns Hopkins University School of Medicine, in Baltimore. “If these mutations are transcribed into new proteins the immune system has never seen before, they can provide a very powerful stimulus for immune recognition.” Oncolytic viruses, such as Amgen’s talimo- gene laherparepvec (TVEC), a recombinant herpes simplex virus 1 (HSV-1) engineered to grow selectively in transformed cells, may also stimulate the immune system through lysis of cancer cells and release of tumor- associated antigens. As monotherapy, TVEC has elicited modest responses in trials to date, but boosting the immune system, by target- ing an inhibitory co-receptor, could improve its efficacy. TVEC is already undergoing a combination trial with Yervoy, which targets cytotoxic T-lymphocyte antigen 4 (CTLA-4). Merck now wants to see how it works with a PD-1 inhibitor. “I think that it’s still way too early to walk away from technologies, com- pounds and platforms that do not appear to be overtly active,” says David Mauro, direc- tor of clinical oncology at Merck Research Laboratories. “Much of what we’re doing in this space is signal detection,” he says. Deciding where to look for hints of efficacy remains a challenge at this stage, however, as a solid scientific rationale for many combi- nations is still in short supply. “The primary challenge is there are so many potential com- binations, there needs to be a way to priori- tize or sift through the possibilities for clinical testing,” says Topalian. Preclinical research, using patient samples to dissect resistance pathways that arise during drug therapy, is providing some clues. For example, one recent Immune-checkpoint pathways can modulate T-cell responses by influencing communication between T cells and antigen-presenting cells. (Reproduced from Nat. Rev. Cancer 12, 252– 264, 2012) NEWS npg © 2014 Nature America, Inc. All rights reserved.

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Page 1: Immune-checkpoint inhibitors march on, now in combinations

nature biotechnology volume 32 NumBeR 4 APRIl 2014 297

in this sectionCancer trial assesses clinical benefit of gene-targeted drugsp306

Fraunhofer to mine Sanofi microbial collectionp305

Leptin therapy gets FDA green lightp300

study suggests that inhibition of extracellular signal–regulated kinase (ERK) may overcome combined resistance to BRAF and MEK inhi-bition (Cancer Res. 4, 61–68, 2013). Another suggests that inhibiting autophagy, a cell sur-vival mechanism induced in response to stress, with the anti-malaria drug hydroxycholoro-quine can achieve a similar outcome (J. Clin. Invest. 124, 1406–1417, 2014). A third found that inhibition of PD-1 and another immune checkpoint, T-cell immunoglobulin-3 (Tim-3), could improve the immunogenicity of cancer vaccines, as both proteins, which function as inhibitory T-cell co-receptors, are upregulated following vaccine administration (Cancer Res. 74, 1045–1055, 2014).

Although the hypotheses that are now being tested in the clinic are becoming richer, in terms of supporting data, not every good idea will get that far. “The challenge

Immune-checkpoint inhibitors march on, now in combinationsThe pace of deal-making in cancer immuno-therapy has picked up sharply since the start of the year. In February, Merck, of Whitehouse Station, New Jersey, teamed up with Pfizer, Incyte and Amgen, to begin phase 1/2 trials of its programmed cell death 1 (PD-1) inhibi-tor MK-3475 in four different combinations, while entering a large-scale discovery and development alliance with nanobody devel-oper Ablynx of Ghent, Belgium (Table 1). Meanwhile, New York–based Pfizer and Johnson & Johnson, of New Brunswick, New Jersey, and MedImmune, the biologics arm of London-based AstraZeneca, are all tap-ping into the immunotherapy expertise of the University of Texas MD Anderson Cancer Center, in Houston, to deepen their under-standing of the underlying biology (Box 1). Although each of these initiatives is early stage and exploratory, taken together they demonstrate the potential big pharma sees in developing immune-checkpoint modulators for cancer combined with vaccines, chimeric antigen receptor technology, cytokine-neutral-izing antibodies and small-molecule drugs.

Immunotherapy and targeted therapy have largely developed in parallel universes up to now. As they mature, the prospect of their convergence is becoming tangible. Big pharma companies are forging deals in the space, hop-ing to make up ground on New York–based Bristol-Myers Squibb (BMS), who developed the first approved checkpoint inhibitor, Yervoy (ipilimumab), a human monoclonal antibody targeting cytotoxic T-lymphocyte activator-4 for treating metastatic melanoma (Nat. Biotechnol. 29, 375, 2011).

Despite the current fascination for combin-ing immunotherapies with different agents, the whole field remains at an early stage of devel-opment. Some trials have already delivered results, although most regimens have not yet been optimized. A combination of Zelboraf (vemurafenib), a BRAF inhibitor marketed by Basel-based Roche, and BMS’s Yervoy caused liver toxicity problems in melanoma patients, although these were reversible (N. Engl. J. Med. 368, 1365–1366, 2013).

Pairing a targeted agent with one or more immune-checkpoint agents appears to offer

complementary mechanisms of action. A kinase inhibitor can reduce the tumor load before an immune response has time to develop, and an activated immune system may then mop up residual cancer cells that have become resistant to the drug therapy. The effect could be particularly pronounced in melanoma, which has a very high mutation frequency. “Those mutations actually create opportunities for the immune system to recog-nize the cancer,” says Suzanne Topalian, direc-tor of the melanoma program at the Kimmel Cancer Center at Johns Hopkins University School of Medicine, in Baltimore. “If these mutations are transcribed into new proteins the immune system has never seen before, they can provide a very powerful stimulus for immune recognition.”

Oncolytic viruses, such as Amgen’s talimo-gene laherparepvec (TVEC), a recombinant herpes simplex virus 1 (HSV-1) engineered to grow selectively in transformed cells, may also stimulate the immune system through lysis of cancer cells and release of tumor-associated antigens. As monotherapy, TVEC has elicited modest responses in trials to date, but boosting the immune system, by target-ing an inhibitory co-receptor, could improve its efficacy. TVEC is already undergoing a combination trial with Yervoy, which targets cytotoxic T-lymphocyte antigen 4 (CTLA-4). Merck now wants to see how it works with a PD-1 inhibitor. “I think that it’s still way too early to walk away from technologies, com-pounds and platforms that do not appear to be overtly active,” says David Mauro, direc-tor of clinical oncology at Merck Research Laboratories. “Much of what we’re doing in this space is signal detection,” he says.

Deciding where to look for hints of efficacy remains a challenge at this stage, however, as a solid scientific rationale for many combi-nations is still in short supply. “The primary challenge is there are so many potential com-binations, there needs to be a way to priori-tize or sift through the possibilities for clinical testing,” says Topalian. Preclinical research, using patient samples to dissect resistance pathways that arise during drug therapy, is providing some clues. For example, one recent

Immune-checkpoint pathways can modulate T-cell responses by influencing communication between T cells and antigen-presenting cells. (Reproduced from Nat. Rev. Cancer 12, 252–264, 2012)

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298 volume 32 NumBeR 4 APRIl 2014 nature biotechnology

in brief

NEWS

“i don’t care who you are, you should be going public right now because the capital is there.“ Oleg Nodelman, founder and managing director of EcoR1 Capital of San Francisco Bay area, speaking at the BIO CEO and Investor Conference, New York, 14 February 2014.

“Governing naples certainly requires a sparkle of madness.” Tommaso Sodano, vice mayor of Naples, defends his city’s use of public funds to genotype the city’s dog population. The effort is an attempt to cut down on people who fail to clean up after their dog on the city streets. (The New York Times, 22 February 2014)

“Monsanto Develops Hardier Strain Of Corn That Yields Four Times normal Litigation.” The Onion spoofs on Monsanto. (The Onion, 26 April 2014)

in their words

Ablynx checkpoint agents lure Merck

In February, Belgian company Ablynx sealed a deal with Merck of Whitehouse Station, New Jersey, to co-develop several nanobody drugs directed at immune checkpoints to treat

cancer. This and a flurry of recent deals, including Bristol-Myers Squibb’s pact with Five Prime Therapeutics and Novartis’ acquisition of CoStim, confirm the industry’s infatuation with checkpoint modulators. “Merck wants in, too,” says Mick Cooper, a healthcare analyst at London–based Edison Investment Research, particularly after the approval of checkpoint inhibitor Yervoy (ipilimumab). “Ablynx is enabling Merck to potentially have products that could be differentiated from others,” Cooper says. Ablynx will receive €20 ($27) million in cash and up to €10.7 ($14.8) million to fund research over three years. The Ghent-based biotech is eligible to receive up to €1.7 ($2.3) billion in milestones and royalties. Immune checkpoints, such as PD-1, are involved in suppressing immunity so drugs that block these pathways can reactivate the immune response. Whereas most immune-checkpoint blockers in development are monoclonal antibodies (mAbs), nanobodies are fragments of llama antibodies based on a single monomeric variable antibody domain—and one-tenth the size of mAbs. Ablynx’s platform links several nanobody proteins to form a molecule that can target more than one protein. “Most companies can’t do that [with their technology],” Cooper says. The collaboration expands a €456 ($624)-million deal signed between the two companies in 2012 to discover drugs to modulate ion channel activity to treat neurological disease. Gunjan Sinha

Capital, who co-founded the company in 2012, along with MPM’s Robert Millman and scientific founders Arlene Sharpe and Vijay Kuchroo, both of Boston-based Harvard Medical School, and Gordon Freeman, of Dana-Farber Cancer Institute. “That’s all doable, but it gets very expensive if you start to go through that multifactorial develop-ment process,” Evnin says. Moreover, should the development effort lead to a successful

is how focused can you be versus how broad do you want to be,” Mauro says. The scale of that task was a major factor in Cambridge, Massachusetts–based CoStim’s decision to sell out to Novartis at this stage in its devel-opment. “In order to stay competitive— particularly when you’re thinking about combinations—you have to be willing to pursue a multipronged development path-way,” says Luke Evnin, of Boston-based MPM

Table 1 Summary of recent cancer immunotherapy agreementsCompany Partner Details indications Dates

Bristol-Myers Squibb

Five Prime Therapeutics (S. San Francisco, California)

Drug discovery and development agreement ($41-million upfront plus equity investment; $9.5-million research funding; $300-million milestones) centered on targets in two immune- checkpoint pathways

Multiple cancers 3/17/14

Novartis CoStim Acquisition, adding late-stage discovery immunotherapy programs to Novartis pipeline

Multiple cancers 2/17/14

Pierre Fabre (Castres, France)

Aurigene (Bangalore, India) Licensing deal for AUNP-12, a peptide-based PD-1 inhibitor

Multiple cancers 2/13/14

Merck Ablynx (Ghent, Belgium) Deal on discovery and development of immune checkpoint–targeting nanobodies, including bi- & trispecific molecules

Multiple cancers 2/3/14

Merck Pfizer Collaboration on phase 1/2 studies of PD-1 inhibitor MK-3475 + tyrosine kinase inhibitor Inlyta (axitinib); and MK-3475 + PF-05082566, a 4-1BB agonist

Renal cell carcinoma; multiple cancers

2/5/14

Merck Incyte (Wilmington, Delaware)

Collaboration on phase 1/2 studies of MK-3475 + INCB24360, an indoleamine 2,3-dioxygenase inhibitor

Recurrent non-small cell lung cancer; other advanced cancers

2/5/14

Merck Amgen (Thousand Oaks, California)

Collaboration on phase 1/2 studies of MK-3475 + talimogene laherparepvec, an oncolytic virus

Previously untreated advanced melanoma

2/5/14

Pfizer (New York)

MD Anderson Research collaboration on the development of new immunotherapy combinations

Multiple cancers 1/6/14

AstraZeneca Immunocore Research collaboration & licensing agreement on ImmTacs, high-affinity monoclonal T-cell receptors fused to an anti-CD3 single-chain variable antibody fragment

Multiple cancers 1/8/14

Juno Therapeutics (Seattle)

Fred Hutchinson Cancer Research Center (Seattle); Memorial Sloan-Kettering Cancer Center (New York); Seattle Children’s Research Institute (Seattle)

Close of a $145-million Series A funding round to develop therapies based on chimeric antigen receptors and T-cell receptors

Multiple cancers 1/14/14

Johnson & Johnson

MD Anderson Research collaboration on the development of new immunotherapy combinations

Multiple cancers 1/21/14

Jounce Therapeutics (Cambridge, Massachusetts)

Third Rock Ventures (Cambridge, Massachusetts)

$47-million Series A funding to develop undisclosed first-in-class immunotherapies

Multiple cancers 2/14/13

AstraZeneca (London)

Amplimmune Acquisition ($225 million upfront + $275-million milestones), adding preclinical PD-1 inhibitor AMP-514, plus preclinical molecules targeting B7 pathway to AstraZeneca pipeline

Multiple cancers 8/26/13

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nature biotechnology volume 32 NumBeR 4 APRIl 2014 299

outcome, having multiple drugs under one roof allows a company to “control the eco-nomics of the package,” he says. “I think you need to control both elements of the combi-nation in order to get rational pricing.”

The potential of combining immunothera-pies is evident from the promising responses seen in interim data last year from a phase 1 combination trial in advanced melanoma patients of BMS’s Yervoy and its phase 3 PD-1 inhibitor nivolumab. Optimally dosed patients achieved a 53% response rate, which is considerably higher than—albeit not directly comparable to—the response rate of patients in earlier trials, who received either one of the two drugs as monotherapy. That combination is now undergoing a phase 3 trial, and both agents are also being tested in numerous other combinations.

Extending the early findings from mela-noma into other cancer indications is under-way in earnest as well. “Now we’re seeing signals in tumors that we would not have expected, based on what we thought we knew about the biology,” says Mauro.

Safety is, as ever, a major issue. As a single agent Yervoy already carries a heavy load of side effects. In the phase 1 combination study, 53% of patients on a concurrent regimen, which is also being applied in the phase 3 trial, experienced grade 3 or grade 4 (i.e., severe to life-threatening) treatment-related adverse events. The problems seen were “qualitatively similar to previous experience with monotherapy and were generally revers-ible,” the study’s authors note (N. Engl. J. Med. 369, 122–133, 2013). Just as drug devel-opers seek synergies between two agents, they also try to avoid overlapping toxicities that could have a greater than additive effect.

Much of this work is necessarily empirical. “Unfortunately, the animal models, I would say, are only loosely predictive of the side effects we see in humans,” says Topalian. Yet monitoring patients closely and learning how to intervene has been a mainstay of clinical cancer care since the dawn of chemotherapy, says Padmanee Sharma, of MD Anderson. With immunotherapy, she notes, adverse events tend to be of the ‘itis’ variety—such as hepatitis, colitis, dermatitis and uveitis—and clinicians are learning how to manage these problems with steroids, without abolishing the efficacy of the immunotherapy. But hav-ing an early insight on which patients are at risk of developing problems would help. “I would say biomarkers are an issue right now,” Sharma says. “The biomarker question has to come down to how do we manage patients for safety and toxicity.” Addressing different cancers with different therapeutic combina-tions remains a long game. But the shape of the research agenda is now becoming clearer.

The FDA’s recognition of the grow-ing importance of combination therapy is reflected in draft guidance it issued on February 24, which proposes to extend exclu-sivity provisions for fixed-dose combinations that contain one new chemical entity, from three to five years. It is seeking responses to its consultation by April 25.

Despite the rapid progress, the whole field remains at an early stage of develop-ment. “If we didn’t find another drug that was active in melanoma for another 20 years, we could still have full careers in sequencing and sorting the drugs that we have now,” says Ryan Sullivan, at the Dana-Farber Cancer Institute, in Boston.

Cormac Sheridan Dublin

Box 1 Big pharma flocks to MD Anderson

Three research agreements MD Anderson Cancer Center entered in quick succession, with Pfizer, Johnson & Johnson and MedImmune, confirm the central role it now occupies in cancer immunotherapy, following the move there of cancer immunotherapy pioneer Jim Allison in November 2012 (Allison pioneered antibody targeting of the checkpoint CTLA-4 that resulted in Yervoy). Specific details were not disclosed, but the agreements will give each company access to the expertise at the center in a relatively informal fashion. “We’re not led by contracts and legal terms so much,” says MD Anderson’s Padmanee Sharma. “They’re meant to be broadly based and open minded.” There is a risk-and-reward sharing dimension to each of the two agreements, should any joint projects give rise to commercially valuable therapies. But defined outcomes are not locked into either deal. “It’s really open-ended—it can change, and it can be very flexible,” she says. The agreements are distinct from a more traditional drug licensing deal, worth up to $335 million, which MD Anderson entered in July 2012 with GlaxoSmithKline. That involved a set of antibodies that mimic OX40L, a ligand for the stimulatory co-receptor OX40. Yong-Jun Liu (now at the Baylor Institute for Immunology Research in Dallas), uncovered an additional role for OX40L, in shutting down interleukin 10–producing regulatory T cells, which play a role in maintaining peripheral immune tolerance (Proc. Natl. Acad. USA 103, 13138–13143, 2006). CS

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