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Ever since ipilimumab (Yervoy) gained FDA approval in 2011 for the treatment of metastatic melanoma, the immune checkpoint blockade strategy that the agent employs has been an intense focus of interest in research and pharmaceutical circles.
Jonathan Skipper, PhD
Ever since ipilimumab (Yervoy) gained FDA approval in 2011 for the treatment of metastatic melanoma, the immune checkpoint blockade strategy that the agent employs has been an intense focus of interest in research and pharmaceutical circles. Now, the concept of manipulating the immune system’s regulatory processes to attack cancer is branching out in new directions.
Ludwig Cancer Research recently announced plans to explore three monoclonal antibodies aimed at two different checkpoint modulators. The term encompasses antibodies devised to block receptors that inhibit the immune response against cancer as well as those that bind and activate receptors known to have the opposite effect.
Launched in 1971, Ludwig Cancer Research is a global network of more than 600 researchers located on four continents working collaboratively to advance the diagnosis, treatment, and prevention of cancer. The network has also established several partnerships with other research institutions and private companies to translate laboratory discoveries into clinical applications.
In March, Ludwig Cancer Research and Agenus Inc, a Massachusetts- based company, said they would advance a novel CTLA-4 antagonist (inhibitor) and two GITR agonists (activators) into preclinical development. In addition, the partners are working on other checkpoint modulators, including OX40 agonists and antagonists of LAG-3, TIM-3, and PD-1 (Table). Ludwig has established similar partnerships with several other companies, including MedImmune, CureVac, and Recepta Biopharma, to advance immunotherapies and other interventions. It has a longstanding partnership with the Cancer Research Institute (CRI) to establish clinical trials with immunotherapies. And, it has also spun off many biopharmaceutical firms in its efforts to help ensure that Ludwig discoveries are translated into products that ultimately benefit cancer patients. The Agenus antibodies, which are derived from human immunoglobulin genes, were selected using platform technology that 4-Antibody AG, a European biopharmaceutical company, created. Agenus acquired 4-Antibody in January.
Two of the targets covered by the partnership, CTLA-4 and PD-1, have become quite familiar in oncology drug development. CTLA-4 is the target of ipilimumab, a monoclonal antibody that blocks CTLA- 4 from binding with its ligands to dampen T-cell activation. PD-1, which interacts with its ligand PD-L1 to shield tumors from an immune response, has become a top target for anticancer agents, particularly in non-small cell lung cancer.
The focus on checkpoint modulators is in keeping with Ludwig’s rich history in the field of immunotherapy. The late Lloyd J. Old, MD, who helped establish the Ludwig Institute and held several leadership posts over the years, is widely recognized as one of the most important figures in modern tumor immunology. His pioneering work in the field includes exploring bacille Calmette-Guérin as an anticancer therapy, discovering tumor necrosis factor, and a series of discoveries that significantly advanced the immune surveillance hypothesis, the theoretical framework on which modern immunotherapy rests.
Among the scientists working with the network today is Jedd D. Wolchok, MD, PhD, director of the Ludwig Collaborative Laboratory and associate director of the Ludwig Center at Memorial Sloan Kettering Cancer Center in New York City (Ludwig MSK). Wolchok played a major role in the clinical studies that led to the FDA’s approval of ipilimumab. His current projects include exploring GITR and OX40, which are activating receptors in the immune system.
In an interview with OncologyLive, Jonathan Skipper, PhD, executive director of Technology Development for the Ludwig Institute for Cancer Research, discussed efforts to target checkpoints.
OncologyLive: Why is there so much excitement about immunotherapy in the research community?
Skipper: I believe it is in part because of what we’ve seen from the first set of results using immune modulators to treat cancers, and in part because of the promise such therapies hold. What generates particular excitement is the prospect of harnessing the body’s own defense systems to control cancers, since those mechanisms are highly adaptive and have the potential—with some help—to address the extraordinary adaptability of most malignancies. This means that the responses generated by the right immunotherapy, or the right combination of such therapies, could induce durable control and perhaps, in some cases, even a cure of some cancers. Indeed, long-term studies of patients who responded to ipilimumab seem to suggest that this mode of checkpoint blockade can sometimes induce complete control of cancer for periods lasting several years.
We’ve been hearing these agents described as “checkpoint inhibitors.” Ludwig is using the term “checkpoint modulators.” Is this more appropriate terminology?
Checkpoint is a generic term. Some of those targets are inhibitory, others are stimulatory or costimulatory targets and are involved in activating the immune response. Since either effect might be induced, depending on the target and the type of therapy used, I think “modulation” is the better general term for this type of therapy.
Ideally, you can imagine the agents being used in complementary fashion, and such combinations are subjects of intense study at Ludwig. This is because one would anticipate—and there are clinical data to support this—that you would have a greater tumor effect by combining classes of agents. We see evidence of that in the studies that Jedd Wolchok and his colleagues have done, where they have combined agents targeted to both PD-1 and CTLA-4 to treat advanced melanoma. Both those therapies disabled signals that inhibit immune responses but, even in that situation, they did so in distinct ways and, in early trials at least, had impressive effects. Such combinations can have additive effects on anti-tumor immune responses.
Then there are two classes of receptors—activating receptors and inhibitory receptors?
Classes in terms of activating and inhibitory receptors, yes. Various receptors and ligands play complementary roles in stimulating appropriate immune responses when the body is challenged by some sort of pathological assault. Once you’ve initiated that immune response, and after you’ve dealt with whatever the initiating mechanism was, whether it was a virus, a bacterium, or even a tumor, you then want to dampen the immune system so that you minimize the collateral damage to healthy tissues and reduce the risk of eliciting self-reactivity or auto reactivity. Checkpoints like CTLA-4 and PD-1 presumably have evolved to provide that “stand down” signal to the immune system. So there are positive signals, negative signals, and signals that coordinate and control them. Research into the mechanisms of these interconnected regulatory processes is ongoing at Ludwig and a number of other research centers.
When we talk about CTLA-4, in particular, we say the strategy “takes the brakes off the immune system.” If an agent were targeted at an activating receptor, what would be the correct description?
I think it would be “pressing the accelerator” or “stepping on the gas.”
How is Ludwig Cancer Research developing checkpoint modulator antibodies?
We originally established a partnership to develop therapeutic antibodies with 4-Antibody, a biotech that was acquired by Agenus. The aim of the collaboration is to utilize their technology to generate antibodies against a panel of targets that our investigators are interested in working on.
TNF indicates tumor necrosis factor; Treg, regulatory T cell.
1. Melero et al. Clin Cancer Res. 2013;19(5):997-1008. 2. Takeda et al. J Immunol. 2004;172(6):3508-3589.
3. Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264.
Our investigators at Ludwig MSK have considerable experience in designing and validating the sophisticated kinds of assays required to screen these antibodies and identify lead candidates that have the required functional characteristics for each of the targets. We will look to Agenus to carry out some of the routine drug development activities, such as cell-line development, toxicology, and drug manufacturing.
Once the antibodies become available as clinical agents, we would look to evaluate them in clinical trials. Ludwig’s Clinical Trials Management Group would design and run trials together with some of our clinical investigators in the United States, Europe, and even Australia.
Which targets in the Agenus partnership are most advanced in terms of clinical development?
The candidates so far selected for development are two antibodies that bind and activate GITR, a molecule that stimulates T cell responses, and one that inhibits CTLA-4. Candidates against OX40, LAG-3, PD-1, and TIM-3 are currently in the process of being screened and selected.
OX40 stimulates anticancer immune responses, so we’re working with Agenus to develop agonistic antibodies against that molecule and inhibitory antibodies against LAG-3, PD-1 and TIM-3, which inhibit anticancer responses. There is much that depends on Agenus, but we would hope they will be in a position to file an investigational new drug (IND) application on the two main candidates toward the end of 2015. Following IND approval, Ludwig would begin clinical trials.
Would that be a new antibody aimed at CTLA-4?
Yes. It would be a totally novel antibody.
Would that also be a therapy for melanoma?
Not necessarily. Melanoma is the setting where we have initially seen the greatest success but there is activity in other indications. In fact, in a clinical partnership we have with CRI and the company MedImmune [part of AstraZeneca], the immune checkpoint antibodies include agents against CTLA-4, PD-1, and PD-L1. We are combining PD-L1 and CTLA-4 antibodies in six different solid tumors. The idea is to explore the activity of that combination outside of melanoma in novel disease indications.
Are checkpoint antibodies considered active or passive immunotherapy?
The principle is that they are activating the adaptive immune response. They are activating T cells. They are an antibody-based treatment, but they differ from the traditional targeting antibodies, which are more passive in that they are given in large quantities to target a tumor.
What do you think is important for practicing clinicians to know about immune-targeting antibodies at this point?
I think these are very exciting new therapies. There have been tremendous findings of very positive clinical activity with some of these agents. I suspect in the next decade or so they are going to become central to many of the current standards of care, probably in combinations, or in addition to the existing standards of care, or with radiotherapy and even chemotherapy. Those are the kinds of clinical trials that we’re running right now using CTLA-4 agents, and PD-1 and PD-L1 agents, and ultimately with some of the newer antibodies.
Clearly, more has to be done, though. Toxicity issues need to be addressed. Exactly how we combine some of these agents and what we combine them with is research that is ongoing within Ludwig’s extended network and elsewhere.
How do the toxicities with immune-modulating agents compare?
The toxicities are typically going to be immune mediated, so they are going to have similar principal mechanisms. So the use of steroids and the like, which are currently the way that these adverse events are managed with CTLA-4 and PD-1 therapies, will be useful in the context of the other agents as well.
I do think that combining some of these immunotherapies is going to take better understanding of how best to do so in a safe way.
Toxicities will need to be managed. We’ve learned an awful lot from the development of CTLA-4 blockers and even the PD-1 blockers, and the early-stage trial completed last year by Jedd Wolchok and his colleagues, which evaluated a combination of the two for melanoma, assessed toxicity of the combined regimen. Having an understanding of the kinds of toxicities we’re going to see, I think it’s quite interesting to compare the reaction now with the toxicities that were first seen with CTLA-4, where there were some surprises—or maybe we just didn’t know what we were going to see. Similar toxicities were seen with some of the PD-1 and PD-L1 blockers.
Having the previous knowledge, these [adverse events] could be managed much more safely and much more carefully. There is this impression out there that blocking PD-1 is less toxic than blocking CTLA-4, but I think PD-1 was developed in a setting where there was more experience dealing with the toxicities, since anti—CTLA-4 antibodies had already been extensively studied in clinical trials.
Has the universe of checkpoint modulators been defined?
Certainly not. First, there are other kinds of targets we have not discussed that are already generating interesting immune-modulating strategies. For example, ITEOS Therapeutics, a biotechnology company in Belgium that was spun off by Ludwig, is developing small-molecule drugs that inhibit two intracellular enzymes—IDO1 and TDO2—that are constitutively expressed in most types of cancer.
When expressed at high levels, these enzymes boost the degradation of the amino acid tryptophan, which is essential to the effective immune surveillance of tumors. So these molecules might prove to be of great use in combination with other immunotherapies.
Second, our understanding of immune regulation is quite extensive, but I’m sure we have much left to learn. As we learn more, new targets for therapeutic modulation will doubtless come into focus. And I think there is certainly plenty of additional work to be done on some of the chemokine receptors; some of those may have immune effects in certain settings. A Ludwig collaborator at the University of Cambridge in the United Kingdom is looking at CXCR-4, where it appears that if you antagonize that particular chemokine receptor in a pancreatic cancer model you can overcome stromal cell—induced local tumor immunosuppression.
Then we are really at the beginning of the checkpoint story?
Yes, I would agree with that.