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With First-In-Class Iovance BLA Pending, TIL Therapies on Cusp of Commercialization

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NEW YORK – Industry and academic drug developers are expecting tumor infiltrating lymphocyte (TIL) therapies to attract increasing commercial interest in coming years, especially since Iovance Biotherapeutics may soon pave a regulatory path for other companies by filing a biologics license application for its TIL product, lifileucel, with the US Food and Drug Administration sometime this year.

Harvested from a patient's biopsied tumor, expanded ex vivo with the help of interleukin-2, and reinfused as a one-time treatment, TILs have the potential to drive aggressive cancers into durable remissions. The TILs that are harvested from patients' biopsies for treatment are T cells that have recognized and infiltrated a tumor but, be it due to the tumor microenvironment or other suppressive factors, have not been able to kill off the cancer.

The act of expanding these cells and reinfusing them in greater numbers after the patient has undergone a lymphodepleting regimen is the crux of TIL therapy. Throughout the course of roughly 30 years since the treatment was first developed in the surgery branch of the National Cancer Institute, TILs have become an established method of treating advanced solid cancers that are unresponsive or refractory to other immunotherapies or targeted treatments.

But despite being a longstanding research interest at the NCI and academic institutions, such as MD Anderson Cancer Center and the Moffitt Cancer Center, no pharmaceutical or biotech company has successfully turned TILs into a commercial product. The reason, according to Jason Bock, the VP and head of biologics development at MD Anderson and an Iovance consultant, TIL therapy doesn't easily fit into a standard drug development framework.

Defining the product

A TIL therapeutic product can have hundreds of T-cell receptors primed against different neoantigens specific to a patient's tumor, and when the expanded TILs are reinfused into that patient, his or her immune system can determine which target and TCR will lead to the intended cytotoxic effect against the tumor. This inherent multivalency is widely considered an advantage for TIL therapies, Bock said, but it is also part of the reason why drugmakers have found TILs difficult to define as a therapeutic product that they have innovated and can sell at a premium price.

Currently marketed immunotherapies are designed to recognize and go after a specific target, and their developers are credited with bringing this design to fruition. TILs, however, already know their targets. Without the need for human engineering, TILs recognize multiple antigens and are uniquely personalized to a patient, since they are a patient's own immune cells that have already recognized and invaded cancer cells. 

"Both the strength and the challenge of TIL [therapy] is that it's a less-defined product [than other cell therapies]," Bock said. "Because the specificity is inherent to the product."

For example, CAR T cells recognize one or two specific antigens and are genetically engineered by a drug developer to do so. "CAR T is essentially like a souped-up monoclonal antibody. We know the specificity, we've programmed it [to target] CD19," which the treatment uses to recognize and kill cancer cells, Bock said. "And we can measure all that."

These inherent features of TILs that make it a good therapeutic, may also be the reason why they've remained in the lab for so long and CAR T-cell therapies reached the market for treating hematologic malignancies despite being discovered after TILs.

Although TILs defy the traditional definition of a drug, Bock expects that if Iovance is able to take its TIL product through the FDA, it will give shape to the regulatory parameters that TILs will have to meet to demonstrate safety and efficacy. San Carlos, California-based Iovance, for its part, sees the whole process — from when the biopsy is taken from a patient's tumor to when the TILs are reinfused after a lymphodepleting chemotherapy regimen, followed by a boosting IL2 infusion — as its "product."

"The patients are receiving their own cells expanded and rejuvenated, while the manufacturing process and the method for growing the TIL, as well as the culture and media used, creates the final product," Iovance CEO Maria Fardis wrote in an email, explaining that the company currently has over 20 US and international patents covering its TIL therapy's "composition of matter and methods of treatment" using the company's manufacturing process.

Much of Iovance's intellectual property is licensed from the NCI. The original deal was inked in 2011, when the company was a privately held firm, called Lion Biotechnologies. The company has since merged with Genesis Biopharma, gone public, changed its name to Iovance, and cut about a month off the processing and manufacturing time required of the original NCI TIL therapy.

The NCI's "processes for growing and manufacturing TIL were not intended to be scalable, centralized, and reproducible for a broader patient population," Fardis wrote. "Iovance took the initial NCI license and developed the manufacturing process to a robust, potentially commercial process using the know-how at the company."

According to a presentation that Fardis made to investors during the B Riley Oncology Investor Conference earlier this month, the first-generation TILs that Iovance licensed from the NCI took about six to seven weeks to manufacture. The product that Iovance is now planning to file for approval takes 22 days to produce for each patient from start to finish, and the company hopes to bring a product with a 16-day turnaround time into the clinic as well.

Clinical efficacy, advantages

The advantage of TIL therapies are in the durability of patient responses and the treatment's multivalency, MD Anderson's Bock explained, citing the case of one patient who experienced complete tumor regression within about three months of his TIL infusion. The patient proceeded to remain in remission for five years, until a mass showed up in the liver. A biopsy showed that the mass — a necropsied tumor — had indeed been a recurrence, but the TILs from five years earlier had killed it off. The TCRs that the TILs used to attack the reemerged tumor, he said, were different TCRs than those involved in fighting the original tumor.

"Those TILs that we infused were still surveying that patient," Bock said. "And when he had a recurrence, [the cancer] at first got a head start … but then the TILs recognized it and expanded and took care of it."

This is possible with TILs because they have many targets, and it also illustrates the limitation of CAR T-cell therapies. "That’s never going to happen with a CAR T, because a solid tumor has all of this micro-heterogeneity and will do all of these things to evade the immune system, especially if you only have one target," Bock explained.  

Data from the Phase II clinical trial that Iovance wants to submit to the FDA for approval of lifileucel in metastatic melanoma are not mature enough to show the effects of the treatment many years post-infusion. As of January, the company reported that after more than two years of follow-up, the duration of response in one of the cohorts had not been reached. The confirmed overall response rate among a cohort of 66 patients was 35 percent. Evaluation of an additional cohort of 68 patients is still ongoing, but early data showed a 32 percent response rate after around 5 months of follow-up.

The patients enrolled in the trial had all received prior anti-PD-1 immunotherapy and targeted BRAF-MEK inhibitors if their tumors harbored BRAF V600 mutations. Many had also received anti-CTLA4 immunotherapy. After patients have exhausted these options, only chemotherapy is left. 

"There is a role for TILs in melanoma patients who have progressed beyond immune checkpoint blockade," said Patrick Hwu, the president and CEO of the Moffitt Cancer Center, which is collaborating with Iovance on a separate TIL trial. "That's really important. … We really need something for that population of patients."

Iovance may also seek approval for lifileucel in heavily pretreated cervical cancer. This is based on the results of a Phase II clinical trial in which 44 percent of 27 patients saw their tumors shrink and the median duration of response was not yet reached at around seven months.

Although the melanoma and cervical cancer programs are furthest along, Iovance is also working on developing TILs for other solid tumors, including head and neck cancer and non-small cell lung cancer. In the latter setting, Iovance is conducting studies independently, as well as with the Moffitt and Bristol Myers Squibb on a study combining TILs with nivolumab (BMS' Opdivo).

In preclinical studies, Hwu has seen the potential benefit of combining a PD-1 inhibitor with TIL therapy over either therapy alone. "It makes sense to combine these together … especially in a disease like lung cancer where anti-PD-1 is already effective in some patients," he said.

'This is where the puck is going'

As of now, Iovance and the FDA are working to come to an agreement about the potency assay that would be used to measure their product. "We continue working with FDA to address [regulators'] comments, including developing and validating other potency assays for potential use in a commercial setting," Fardis said. The company doesn't have a specific date for when it will submit its biologics license application as these issues are still being ironed out, but Fardis remains confident it will be in 2021.

Meanwhile, other companies have advanced their own TIL therapeutic programs. In November, Cambridge, Massachusetts-based biotech Obsidian Therapeutics entered into a collaboration with MD Anderson to advance its own TIL program, and last month, Turnstone Biologics announced it would acquire Myst Therapeutics, a company developing TILs.

"This is where the puck is going," said Bock. "More and more, biotechs are getting interested in TILs … and are starting to invest in that area."

Moffitt's Hwu, who helped pioneer the TIL center at MD Anderson before joining Moffitt in 2020, echoed this prediction. "It's always a positive effect to have a first-in-class product approved," he said. "It gives a little more confidence and courage to others to go in. That's what we need. … We need an infusion of funds and science to make this even better."

Even Fardis was hopeful that an Iovance approval would get the ball rolling for other drug developers. "There is no regulatory precedent for TIL [therapies], so as we navigate through this process, we may set a pathway for several TIL therapies within our own portfolio, as well as for other sponsors," she wrote.

Iovance's product — a "vanilla TIL," as Bock colloquially called it — involves no engineering or tinkering with the T cells before infusion, only expanding and invigorating them with IL2. Accordingly, other companies' TIL therapies that might theoretically move toward commercialization in the coming years could require some added tweaks if they are to boast a competitive advantage.

Some companies are already thinking along these lines. Obsidian, the company that recently collaborated with MD Anderson, is developing a TIL product called cytoTIL that has a regulated membrane-bound IL15 to improve its product's efficacy. Meanwhile, Myst is developing a TIL product that involves a specialized selection method to pick only the most relevant T cells from the tumor sample for expansion and infusion.

Even Iovance is working on its next-generation TIL products, going beyond the "vanilla" bulk TIL approach and working on processes for selecting more potent TILs. Last month, the company signed a deal with Cellectis to develop genetically engineered TILs to work against specific tumor targets.

At both MD Anderson and Moffitt, engineered TILs are in development, too. Hwu and Bock explained separately about efforts at their labs to edit TILs, including using CRISPR, so they are able to overcome factors that might suppress their activity. Specifically, these therapies involve TILs that have been engineered not to respond to a negative tumor microenvironment factor called TGFb.

"There are so many ways for companies to differentiate themselves in this space," Hwu said. "Through selection of different cell types [included in the final product], different ways to grow the cells, different ways to take out genes or put genes in, to make them more scalable … by making the process less manual and more robotic… I really hope they do differentiate themselves. I hope this [potential approval] opens up the field."

Toward commercial readiness

No matter how Iovance and other biotechs choose to define their TIL product, these companies will need to adequately prepare for logistical barriers that will inevitably come with commercializing an autologous, highly personalized cell therapy.

The field has witnessed some of the challenges Gilead's Kite and Novartis, companies with approved CAR T-cell products, have dealt with in the process of harvesting patients' immune cells, cryopreserving them, shipping them to a manufacturing facility, editing them, expanding them, cryopreserving them again, and shipping them back to the patient for infusion. The process requires significant time and resources, and treatment prices reflect this. Both tisagenlecleucel (Novartis' Kymriah) and axicabtagene ciloleucel (Kite's Yescarta) cost upwards of $373,000 for a single infusion.

Steep prices will likely accompany Iovance's TIL product as well, should it be approved, although Fardis emphasized in the B Riley presentation that the pricing for lifileucel has not yet been determined. "I recognize that the agents used as a comparator are not exactly cheap," she acknowledged, adding that if the clinical data are compelling for TILs, a one-time treatment, "payors [will] ultimately have the same goal to make sure that patients receive that appropriate treatment [and] not to have that patient be relapsed or refractory and out of options. Those are more and more expensive settings."

Meanwhile, ahead of FDA approval, Iovance is gearing up to scale the manufacturing process and has invested $85 million in a 136,000 square-foot cell therapy center in Philadelphia, where commercial production is expected to begin in 2022. Iovance is also working with US cancer centers to ensure there are at least 40 TIL treatment centers by the time the product launches. "Our goal is to have treatment centers within a few hours' drive for patients, and we have done extensive mapping work to identify the optimal locations," Fardis wrote. "For the patient, their journey begins and ends at their own treatment center."