Editor's note: This is part one of a two-part series on ways to help more patients realize the promise of immunotherapy drugs.

Jedd Wolchok is apparently not one to rest on his laurels.

As the principal investigator on the 024 study that led to approval of the first commercially successful cancer immunotherapy, CTLA-4 checkpoint inhibitor Yervoy (ipilimumab, Bristol-Myers Squibb Co.) as well as several phase III trials investigating the combination of Yervoy and PD-1 checkpoint blocker Opdivo (nivolumab, Bristol-Myers Squibb Co.), Wolchok has done as much as anyone currently working in oncology for patients.

But in a talk on "perils and promise of combination therapy" at the 2016 annual meeting of the American Society of Clinical Oncology (ASCO), Wolchok told his audience that "the majority of our patients still need better answers."

With the approval of Roche Holding AG's Tecentriq (atezolizumab) for advanced bladder cancer, there are now four checkpoint blockers on the market: Yervoy, Keytruda (pembrolizumab, Merck & Co. Inc.), Opdivo and Tecentriq.

For the minority of patients in which they work, those drugs are the proverbial magic bullets, leading to long-term remissions and cures of conditions, like metastatic melanoma, that once had among the grimmest prognoses.

But given that the majority of patients progresses rapidly on monotherapy with checkpoint blockers, "combination therapies have announced themselves as being the next steps forward," Wolchok said.

Like monotherapy with checkpoint blockers, he added, combination therapies are "not a one-size fits all approach. . . . This is going to take some tinkering."

At the ASCO meeting, there were more than 100 abstracts describing various combination regimens of Keytruda alone.

Roy Baynes, senior vice president and head of global clinical development at Merck Research Laboratories, told BioWorld Today that there are "a very large number of potential combinations, so we have to try to do this in a rational way."

There are a number of different categories of drugs that can be combined with checkpoint blockers, and some trials test more than one of them simultaneously.

The first checkpoint blocker, Yervoy, was approved at roughly the same time as Zelboraf (vemurafenib), which targets BRAF mutated melanomas. Between them, the two drugs profoundly changed the treatment landscape for metastatic melanoma when they were approved, and testing them together was a natural next step. The first trial that tested the two agents in combination, however, was halted due to unexpected liver toxicity. (See BioWorld Today, June 7, 2011.)

Those inauspicious beginnings, though, have not inhibited the testing of the combination of targeted therapies and checkpoints, and there are scores of combination trials testing checkpoint inhibitors with targeted therapies.

The targeted therapies that are being tested in combination with CTLA-4 or PD-1-targeted drugs start with the original targeted therapy, Gleevec (imatinib, Novartis AG), continue through Tarceva (erlotinib, Roche Holdings AG/Astellas Pharma Inc.), Sutent (sunitinib, Pfizer Inc.), Tafinlar (dabrafenib, Glaxosmithkline plc.), Xalkori (crizotinib, Pfizer Inc.), Zykadia (ceritinib Novartis AG) and Mekinist (trametinib, Glaxosmithkline plc.), all the way to targeted therapies that are themselves still in early stage clinical trials.

Toxicity rates differ between the types of tumors that are treated. Non-small-cell lung cancer (NSCLC) with immunotherapy leads to toxicity problems in 30 percent of treated patients, while the toxicity rate for melanoma patients is almost twice that, at 55 percent. The reasons are unclear, but one possibility is that NSCLC patients are more immunosuppressed overall, and so immune disinhibition is less likely to go too far and lead to toxicity problems.

The broadest combinatorial category is the combination of checkpoint blockers with other immunotherapies, including other checkpoint blockers. Trials testing Yervoy, which targets a late T-cell checkpoint, and Keytruda, which targets an early one, have shown that combining the two led to higher response rates, albeit at the cost of greater toxicity. Ongoing trials are testing whether a reduced dose of Yervoy could reduce toxicity, but Baynes said that at this point, the combination's toxicity is "pretty significant."

T cells have multiple checkpoints, but they also have receptors for activating signals. The extensive role of T cells is illustrative of a broader principle, namely that the immune system is finely balanced between activation and suppression. In tumors, the balance is on the side of suppression – not just on T cells but also in the tumor microenvironment.

Checkpoint inhibitors can be thought of as removing the brakes on T cells. T cells receive more than a dozen inputs regulating their activity that can be either inhibitory or stimulatory. An alternative approach is pressing the accelerator, in the form of co-stimulatory molecules. T cells have receptors for half a dozen such co-stimulatory signals.

Pfizer Inc.'s 4-1BB agonist utomilumab is one such co-stimulatory molecule. At this year's ASCO meeting, phase I data in 23 patients treated with a combination of utomilumab and Keytruda showed several patients with confirmed responses.

There are also different types of T cells – effector T cells, which carry out immune attacks, and regulatory T cells, which inhibit effector T cells. So inhibition of regulatory T cells can have the same net result as stimulation of effector T cells.

A number of co-stimulatory receptors appear to have exactly that dual role, including OX40 agonists and glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists.

Phase I data on one OX40 agonist, MOXR0916 (Roche Holding AG), were presented this spring at the annual meeting of the American Association for Cancer Research. In the first-in-human trial, researchers observed neither dose-limiting toxicities nor a maximum tolerated dose. Toxicities in a combination with checkpoint blockade inhibitors were similar to single-agent toxicities, suggesting that the two interventions have independent mechanisms.

Another strategy that affects regulatory T cells is inhibition of the metabolic enzyme indoleamine 2,3-dioxygenase 1 (IDO-1).

Furthest along clinically is Incyte Corp.'s IDO-1 inhibitor, epacadostat, which is being tested in combination with Keytruda in the phase III ECHO-301 trial for melanoma and has also been tested with other checkpoint blockers across multiple tumor types in phase I and II trials.

Merck is in a partnership with Incyte to explore the combination, but it has also acquired its own IDO inhibitor program as part of its January acquisition of Iomet Pharma Ltd.

Several vaccines are attempting to boost the antitumor immune response by combining checkpoint inhibitors with adjuvants. Data from the phase I trial of Heat Biologics Inc.'s viagenpumatucel-L (HS-110) with Opdivo were presented at the 2016 ASCO meeting, and earlier in the spring, Immune Design presented data from a combination of Tecentriq and its g100 vaccine at the AACR meeting.

Another way to improve the efficacy of immunotherapy is to go for breadth vs. depth and attempt to give T cells more antigens to work with, in the hopes that will stimulate an effective immune response. There is evidence that in bladder cancer at least, the overall mutational load of a patient is a better predictor of whether they will respond to immunotherapy rather than relying on levels of PD-L1 tested using companion and complementary diagnostics to PD-1 and PD-L1 inhibitors.

Imlygic (talimogene laherparepvec, Amgen Inc.) is a therapeutic cancer vaccine based on an oncolytic virus, and became the first oncolytic virus to be approved by the FDA and the EMA in 2015. The vaccine works by specifically infecting and killing tumor cells. But in bursting those cells open, it also creates a lot of antigens for T cells to sample, and the MASTERKEY-265 study is investigating Imlygic in combination with Keytruda.

Finally, mutational load is also increased through the old standbys of cancer treatment – chemotherapy and radiation.

"Unquestionably, there's proof of concept" that such combinations can be beneficial, Baynes said, in part because the cell death caused by cytotoxic therapies do give unleashed T cells a lot of antigens to work with.

To date, though, those studies have been "quite small," and so it remains to be seen whether those benefits are durable, and whether they will replicate in large phase III trials.

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