Cell Therapies in Oncology

Natural killer cells continuously patrol the human body, swiftly eliminating viruses and cancer cells, like sharks in prey-laden waters. Several biotech companies are harnessing the power of these innate immune crusaders in oncology and autoimmune diseases, potentially positioning them as a strong competitor to CAR-T cell therapies.

Unlike CAR-T cells, NK cells don’t need genetic modification to recognize a specific threat — they act broadly without customization. However, some NK companies, such as Fate Therapeutics and Cytovia Therapeutics, enhance NK cells with chimeric antigen receptors to increase precision and efficacy.

NK cell options tend to produce fewer serious side effects, making them particularly appealing in the autoimmune space, which has less risk tolerance than oncology. 

“The advantage of NK cells over a T-cell approach is that NK cells can kill the target cell without causing that runaway cytokine release syndrome,” said Dr. Fred Aslan, president and CEO of Artiva Biotherapeutics. In addition to potential safety advantages, NK cell therapies could disrupt the market by offering a less costly off-the-shelf option that speeds patient access.

A change in direction

Artiva began testing its lead NK cell therapy, AlloNK, in cancer but shifted much of its attention to autoimmune applications following the success of a German CAR-T cell study that showed the technology’s potential to treat serious autoimmune diseases such as lupus. Aslan said NK cells could have similar abilities, and the appeal of a larger market and earlier-stage competition helped drive the pivot. 

Artiva has raised more than $200 million in private funding to back its efforts, in addition to a $167 million IPO in July, reflecting the rising interest in the research area. But the company faces considerable competition from companies such as Dragonfly Therapeutics, which has collaborations with Merck & Co., AbbVie, Gilead Sciences, Bristol Myers Squibb and more.

AlloNK works alongside monoclonal antibodies, such as rituximab or obinutuzumab, in combinations chosen for each target. In patients with cancer or autoimmune disease, NK cells are often diminished or impaired. 

“Although a monoclonal antibody can be effective, it may not have the opportunity to work as well because of poor NK cell function,” Aslan said. “So our basic hypothesis is that by giving large numbers of exogenous NK cells together with monoclonals, we get to the cell we want to kill, and we do it much more effectively, beyond what a monoclonal could do by itself.”

Artiva derives NK cells from umbilical cord blood.

“From one umbilical cord unit, we can make thousands of vials, each with a billion cells,” Aslan said. “Our dose today in the clinic is three billion cells per patient, so that means one umbilical cord could treat over 1,000 patients.” 

The projected cost of vial is less than $1,000, and treating a patient requires roughly three weekly outpatient infusions — ringing up a substantially lower cost compared with CAR-T, which typically costs hundreds of thousands of dollars, Aslan said. 

“Our NK cell therapy could really move the needle from a payer perspective and an access perspective,” he said.

Artiva established an early milestone in autoimmunity as the first NK cell therapy to gain IND approval. AlloNK also received FDA fast-track designation to treat lupus nephritis and relapsed/refractory non-Hodgkin lymphoma of B-cell origin. The company dosed its first lupus patient in April. 

Artiva is also testing a basket set of indications, including rheumatoid arthritis, pemphigus vulgaris and vasculitis. The company is still evaluating AlloNK’s potential in non-Hodgkin lymphoma and relapsed/refractory CD30-positive lymphomas, Aslan said.

“There will be some very compelling treatments coming out of this field and there will be room for a lot of different players here,” Aslan said.

Regeneron has conducted cutting-edge oncology research since checkpoint inhibitors were still the new kids on the block, and before blockbusters like Keytruda and Opdivo were even close to mainstream success. But despite massive scientific and financial achievement in other areas, Regeneron is still playing catch-up in cancer.

Now, the company hopes a packed pipeline will propel its relevance in the next wave of cancer therapies. Dr. Israel Lowy, senior vice president of translational and clinical sciences in oncology, sees a bright future for Regeneron in bringing combinations to the market that could change the disease paradigm even further than their predecessors.

Regeneron is known for playing the long game in the name of next-generation science — and has done so for a long time, Lowy pointed out.

“The company is now more than 35 years old, and for many years, the line on Regeneron was: great science, no products,” Lowy said. “Now we have many products across multiple therapeutic areas, and all along, there was an openness to understanding the key scientific questions in each therapeutic area.”

Still, the company remains an underdog in cancer. Regeneron took off running with immuno-oncology R&D shortly after Lowy, who attended Columbia University with the company’s co-founder and chief scientific officer Dr. George Yancopoulos, joined in 2010. But it wasn’t until its anti-PD-1 therapy Libtayo gained FDA approval in 2018 for squamous cell carcinoma that the company finally had a horse in the immuno-oncology race.

Libtayo was always meant to be just the beginning in immuno-oncology for Regeneron, Lowy said, and leadership recognized that it arrived later to the game than other PD-1 treatments like Merck & Co.’s Keytruda and Bristol Myers Squibb’s Opdivo. While those went on to become major blockbusters, Libtayo had yet to cross the $1 billion mark in 2023 sales.

Regeneron’s ophthalmology blockbuster Eylea and the immunology success of Dupixent carried the company to its spot among the most valuable pharma companies in the world. But now Lowy and fellow company leaders are emphasizing oncology as Regeneron’s next big step, while acknowledging there will be hurdles along the way.

Bispecific blues

Along with a focus on Libtayo’s development, Regeneron was one of the pioneers in creating the first bispecific molecules, Lowy said. The treatments are now part of a promising field in oncology. And although the company was among the first to bring a bispecific antibody to clinical trials, they also learned that being early can come with challenges.

“Because we were the first, we encountered problems like cytokine release and had to explore how to get patients to tolerate the dose,” Lowy said. “It’s become a very competitive area.”

Early bispecific antibodies like Amgen’s Blincyto for leukemia paved the way with a 2014 approval, followed later on by Johnson & Johnson’s Rybrevant for lung cancer and Tecvayli for multiple myeloma, among others.

Regeneron has been a little slower to the punch, getting its first bispecific Ordspono, a T-cell regulator for lymphoma, past European regulators in August. But the company encountered a speed bump in the U.S. when the FDA rejected the treatment despite positive response rates, citing the lack of a confirmatory trial. The U.S. approval process for lymphoma is still underway.

The company has also faced a setback for a bispecific antibody to treat multiple myeloma, which the FDA rejected due to manufacturing concerns.

Outside of blood cancers, Regeneron is studying bispecifics in solid tumors, now a separate department at the company. One of Lowy’s team’s targets is the antibody CD28, which he said was a “third rail” after showing dangerous side effects almost 20 years ago. But knowing it was also a good target, they charged forward, and now have several CD28-based bispecifics in clinical trials, including one for prostate cancer in phase 2.

Going head-to-head

The biggest turning point for Regeneron is still on the horizon, but not far off, Lowy said. The company’s lead oncology candidate is a combination of Libtayo and a LAG-3 inhibitor called fianlimab, which could together rival BMS’ already approved combo Opdualag in melanoma.

Ironically, Lowy helped develop Opdualag when he worked at Medarex before the company was acquired by BMS in 2009, providing the pharma giant with its immuno-oncology portfolio that included Yervoy and Opdivo.

Now, they’re going head-to-head.

“Even though I helped develop it, we’re going to beat it,” Lowy said. 

The phase 3 study in advanced melanoma is expected to read out by the middle of 2025, he said, and will mark a major milestone for the company’s oncology prospects.

Regeneron is also lining up against the “800-pound gorilla” Keytruda with the same combination, Lowy said, seeking to prove superiority in melanoma in another phase 3 study that’s set to wrap in 2026.

On top of the later-stage clinical prospects, Regeneron has also bulked up on cutting-edge collaborations with companies like BioNTech to combine cancer vaccines with a checkpoint blockade. And the acquisition earlier this year of the struggling 2seventy (formerly bluebird) bio’s oncology pipeline has pointed in the direction of cell therapy.

These forthcoming steps for Regeneron will determine whether the company can step up and lead in the next wave of cancer therapies, according to Lowy. And although it’s been a long time coming, he said the science supports a bullish outlook.

“Even in 2010, many people were still skeptical about the ability of these immunotherapies to move the needle,” said Lowy. “But we started figuring out a strategy to build a long-term pipeline that could be a potent force in immuno-oncology.”

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By Cardinal Health

After the launch of the first CAR-T cell therapy in 2017, cell and gene therapies have revolutionized the medical industry, offering fresh hope and new treatment options to patients and families who previously had none.

Even with the promise of these therapies, the path to provider and patient access is far from simple, and the high cost of these therapies as well as the complex administration and logistics components create significant risk for both biopharmaceutical companies and sites of care. Successful launch planning for a cell or gene therapy incorporates defining a distribution channel strategy that streamlines the ordering process for the healthcare provider and mitigates accounts receivables risk to the biopharmaceutical company. A key strategy that biopharmaceutical manufacturers can take to accomplish this is by working with a Third-Party Logistics (3PL) provider to implement a flash title model. In a flash title model, the 3PL provider takes temporary ownership of the therapy product and responsibility for collecting the payment from the site of care, mitigating accounts receivable risk to the biopharmaceutical manufacturer and simplifying the ordering process for the site of care.  

As the industry leading 3PL provider and pioneer of the flash title model, Cardinal Health’s 3PL team has considerable experience working with biopharmaceutical companies to set up and implement a flash title model that meets the needs of each unique cell and gene therapy product. We've outlined below some best practices that biopharmaceutical manufacturers can take to implement a successful flash title model for their therapy – both at launch, and beyond. 

Best Practice 1: Have the terms and conditions set up and filed ahead of time.

Once a biopharmaceutical company has identified, certified, and approved the treatment sites that will be in the treatment network, the list of sites will be sent to the 3PL provider. From there, the 3PL provider will review the sites in the network to make sure that the site has already agreed to the terms and conditions set by the 3PL provider. If there are any sites in the network that are not on file with the 3PL provider, they will work with that site to be onboarded into their network. This is the most intensive part of the onboarding process with the 3PL provider, and not having this step completed ahead of time can delay the accounts receivable timeline for the biopharmaceutical company. Therefore, it is also wise to pick a 3PL provider with a robust site network to minimize the number of sites who need to be added separately.

Best Practice 2: Design your distribution channel to allow for provider acquisition flexibility, where appropriate.

The high sticker price and lengthy reimbursement timelines for cell and gene therapies create significant financial risk for sites of care, particularly for smaller sites. As biopharmaceutical companies look to expand their treatment networks into community settings, biopharmaceutical companies could consider incorporating flexibility in the distribution channel, whether it be through utilizing a specialty pharmacy or implementing an innovative payment model. By allowing for provider acquisition choice, biopharmaceutical companies can mitigate provider risk and improve patient access.

Best Practice 3: Outline various trade scenarios ahead of launch to define the responsibilities for the 3PL partner, pharmaceutical manufacturer, and sites of care.

Unforeseen events can occur throughout the product journey that necessitate a return or require a reorder (i.e. patient passes away before treatment, damage to product). It is important to consider and plan for these scenarios ahead of launch and work collaboratively with each stakeholder (3PL provider, biopharmaceutical company, and site of care) to define their responsibilities and outline the appropriate policies and processes to follow for each scenario. Cardinal Health’s breadth and depth of experience in this field means that they can outline a wide variety of different scenarios, facilitate these conversations, and work collaboratively across all stakeholders to define the best workflow for each scenario.

Best Practice 4: Consider site feedback regarding billing when designing your 340b pricing strategy.

Historically, participating 340b sites of care were initially billed at the wholesale acquisition cost (WAC) for these therapies and then received a rebate after therapy administration. However, as treatment sites become more familiar with each cell and gene therapy and have greater clarity with whether the therapy will be administered in the inpatient or outpatient setting, some treatment sites may want the flexibility to order at the 340b price upfront, versus always having to order at WAC and then go through a credit and re-bill process. It will be important for biopharmaceutical companies to consider site feedback and determine how they will bill 340b participating sites of care ahead of launch and communicate that to the 3PL provider, as it impacts how the 3PL provider sets up customers in their systems and supporting applications to allow the sites to purchase these therapies appropriately.

Working with a trusted 3PL provider such as Cardinal Health can mitigate financial risk to biopharmaceutical companies and streamline the ordering process for sites of care. By considering the best practices outlined in this article, biopharmaceutical companies can work collaboratively with their 3PL provider to set up a flash title model in a streamlined and thoughtful way to optimize the success of their therapy at launch and beyond.  

Atara Biotherapeutics scored a world-first approval for an off-the-shelf T cell therapy when the European Commission greenlit Ebvallo to treat an ultra-rare type of blood cancer in 2022. 

Now, the treatment, known as Tab-cel in the U.S., could soon score a second win as the first allogeneic FDA-approved T cell treatment. 

For Atara’s CEO, Cokey Nguyen, who took the helm in September, the hope is that Tab-cel’s approval is just the beginning of its boundary-pushing milestones. While readying for Tab-cel’s PDUFA date Nguyen, formerly Atara’s chief scientific officer, is steering the biotech as it also advances CAR-T cell treatments in cancer and the next frontier — autoimmune diseases.

Allogeneic treatments are designed to address hurdles with traditional autologous CAR-T technology. Rather than modifying cells taken from patients for a manufacturing process that can take weeks or months, they use cells from healthy donors to pre-manufacture a treatment that’s ready when the patient is, and potentially at a lower cost. 

While off-the-shelf options offer advantages, they also present unique challenges, including the potential to trigger a wayward immune system attack due to the use of foreign donor cells. 

Atara’s novel approach could overcome this roadblock by using donor T cells primed to fight the Epstein-Barr virus that have a biology ideal for modification. In particular, these T cells don’t need gene editing and retain properties that make them less likely to trigger the patient’s immune system. 

“T cells have a very robust DNA damage response and they tend to not proliferate well once you begin to make genetic manipulations,” Nguyen said. 

The treatment approach may also induce a more lasting response than traditional cell therapies, which only holds off disease for more than six months in 30% to 40% of patients. Patients also potentially won’t have to undergo lymphodepletion, which wipes out existing T cells using chemotherapy or another method. 

Tab-cel is being evaluated to treat a relapsed or refractory Epstein-Barr virus-positive, post-transplant lymphoproliferative disease, a blood cancer that can arise after a transplant. 

“The long-term goal is to get this to the finish line … and then transition it to our commercial partner, Pierre Fabre, a multinational conglomerate based in France,” Nguyen said.

The next targets

Atara’s next most advanced candidate is a CAR-T cell therapy dubbed ATA3219 in phase 1 for B-cell non-Hodgkin lymphoma patients whose cancer didn’t respond, or returned after treatment. 

On the autoimmune disease front, Atara is also exploring ATA3219 for Lupus along with another preclinical CAR-T contender, ATA3431, for B cell cancers and autoimmune diseases.

One of the major challenges with the technology in the autoimmune space will be replicating the strong results seen with traditional autologous CAR-T cell therapies while scaling manufacturing capabilities for large patient populations. 

“[It’s about how] we wade through not only the valley of death for the capital markets, but get to clinical proof of concept, and then partner with the right partner to develop these drugs,” he said.

There’s also competition, not only from other companies working on allogeneic candidates, such as Allogene Therapeutics, but newer technologies, such as in vivo CAR-T cell therapies that modify cells inside the body.

But while Nguyen is bringing new leadership to Atara’s effort, he said the company’s short- and long-term visions remain the same. 

“We're trying to take the power of the T cell, bring it to patients and solve really big diseases, multiple sclerosis, severe lupus, all kinds of autoimmune-mediated diseases, as well as still treat cancer,” Nguyen said. “I'm just excited about that opportunity.”

When doctors at Boston’s Massachusetts General Hospital infused a next-generation CAR-T cell therapy into three patients with glioblastoma it produced a stunning response. 

Within days, one patient’s brain tumor shrunk by more than 18%, and by day 69, more than 60%. It stayed in check for more than six months. Two tumors in the same phase 1 trial diminished, and one almost completely disappeared within five days. Unfortunately, all the patients saw their cancer return, and researchers are now searching for ways to create a more lasting effect.

While this early-stage effort wasn’t a cure, it marked one of many positive recent milestones in the quest to treat the deadliest form of brain cancer, also known as glioblastoma multiforme, which accounts for 15% of all brain cancers. Treatment outcomes have been abysmal and stagnant for decades. Only 25% of patients survive more than a year.

“In recent years, immunotherapy has been hailed as the hero for many hard-to-treat oncology indications providing patients with improved prognoses, and it looks as though it could also be the future in glioblastoma treatment,” said Flora Mackay, a senior analyst at Citeline, in an email. “Though attempts to bring immunotherapy to the glioblastoma market thus far have been lackluster, with most agents failing phase 2 studies, there remains a lot of hope for these regimens with investment turning to combinatorial approaches.”

Doctors treating glioblastoma patients typically turn to surgery, radiation, and chemotherapy. Merck & Co.’s temozolomide is the standard option, but more than half of patients don’t respond to it, Mackay said. 

“Prognosis remains dismal with [temozolomide] treatment leading to overall survival of just over one year,” she said.

For those whose tumors come back after the first round of treatment, options are even more scarce. Recurrent glioblastoma has no standard-of-care treatment, but doctors often use a chemo drug called lomustine, which has a response rate of around 10% and a median progression-free survival of around two months. A small subset of patients has two newer, more targeted options, Voranigo, from Servier Pharmaceuticals, and a combination therapy, Tafinlar and Mekinist, from Novartis.

A busy pipeline

While progress has been slow, a robust search is underway for better options. Researchers are conducting more than 640 glioblastoma trials around the world. 

“Immunotherapies represent a significant portion of the pipeline, with just under 50% of ongoing global trials for glioblastoma investigating an agent of immunological therapeutic class,” Mackay said. “The immunotherapies under investigation include CAR-T cells, CAR-NK cells, bispecific CAR constructs, dendritic cell vaccines, immune checkpoint inhibitors and oncolytic viruses.” 

Gilead’s cell therapy division Kite is backing a multi-pronged CAR-T cell approach, now in phase 1, to hit multiple tumor targets to improve success. Within two days, the treatment shrunk tumors in all six patients, while maintaining the effect in some of them for several months.

Mackay pointed out that oncolytic viruses are another promising avenue of treatment. Mustang Bio and City of Hope saw some success in phase 1 with their combination CAR T-cell and oncolytic virus combination treatment IL13Ra2, which extended the lives of people in the trial, including one who has been tumor-free for more than five years.  

“Despite prior tribulations for several of the therapeutic classes, innovation hasn’t ceased with next-generation drugs continuously being explored, as seen with immune checkpoint inhibitors, EGFR inhibitors, and PI3K inhibitors alike,” Mackay said. 

Companies working in this space include Erasca with its EGFR inhibitor, ERAS-801, which got FDA fast track designation in 2023; Black Diamond Therapeutics, with its phase 1 EGFR inhibitor BDTX-1535; and paxalisib from Kazia Therapeutics, a PI3K inhibitor licensed from Genentech. Merck is also testing the versatile blockbuster Keytruda in a phase 2 study for recurrent glioblastoma.

Lingering challenges

While research may be turning a corner, a game-changing option for patients is probably still years away, Mackay said. Glioblastoma treatments have high hurdles to overcome. 

Tumor cells vary, and can pivot quickly to evade the immune system, and researchers also face the challenge of getting drugs past the blood-brain barrier. They’re trying to sneak them past using strategies such as targeted ultrasonic waves, MRI-guided focused ultrasound, efflux transporter inhibitors and nanoparticles, Mackay said. 

“Nanoparticles are small enough to permeate the blood-brain barrier and can be used to encapsulate drugs, delivering the therapeutic payload to glioblastoma tumors that were previously inaccessible,” she said. 

BPGbio is testing a nano-lipid molecule, BPM31510, in combination with vitamin K1 in people just diagnosed with glioblastoma, Mackay said.

But because many promising options are in the early stages, it’s unlikely that a radical transformation in glioblastoma care will occur in the next five years, she said. 

“The challenges posed by this hard-to-treat disease means many agents struggle to progress past phase 2 studies,” Mackay said. “The probability of success for a drug to advance past phase 2 in the glioblastoma space sits at a mere 28% and drops even further to 11.1% for advancement past phase 3 investigations.” 

But there are hopeful signs for the future. 

“While the recent developments in the glioblastoma space symbolize a long-awaited transformation to the previously stagnant paradigm, it is undeniable that further innovation and revolution is urgently needed to improve patient outcomes in one of the highest unmet needs in the oncology market,” Mackay said.

As former chief medical officer for CRISPR Therapeutics, Dr. PK Morrow spent the end of 2023 helping to usher in the first-ever FDA approval for a CRISPR-based treatment. But that wasn’t the only FDA approval on her radar. She was also tracking the status of Takeda Pharmaceuticals’ metastatic colorectal cancer treatment Fruzaqla, the first novel, chemotherapy-free treatment option regardless of biomarker status to win U.S. approval in more than a decade.

“I saw that they were able to leverage that as well as launch almost immediately after getting approval,” Morrow said. “It showed me this company was nimble enough to put forward the needs of the patient.”

Soon after, Morrow took over Takeda’s oncology therapeutic area unit, and has spent the past several months honing and evolving its strategy with a focus on three disease states: thoracic tumors, GI cancers and specific hematologic malignancies such as chronic myeloid leukemia. The company will also home in on four modalities: antibody-drug conjugates, bispecifics, small molecules and cell therapies. “We must adapt to the evolving disease landscape,” she said.

Not long after Morrow’s appointment, Takeda dropped several cancer candidates, including a drug removed from a phase 2 program in relapsed/refractory multiple myeloma. The move was part of the pharma’s pivot away from myeloma and reprioritization of other areas.

“This is a strategic decision based on a number of factors, including the existing data set, the rapidly evolving multiple myeloma treatment landscape and the long development timelines,” Andrew Plump, Takeda’s R&D president said during an earnings call earlier this year. 

Morrow is drawing from not only her history-making experience at CRISPR Therapeutics, but also as a physician at MD Anderson Cancer Center and later, her years at Amgen, where she worked on developing the lung cancer treatment Lumakras, which targets KRAS G12C, a mutation that had been considered “undruggable” for decades.

“When I came to Takeda, I knew how to successfully develop therapies that met an unmet need,” she said. “You also have to have courage of conviction to know which therapies you really want to accelerate the development of.”

Here, we spoke to Morrow about her focus at Takeda and the company’s revamped oncology strategy.  

This interview has been edited for brevity and style.

PHARMAVOICE: How are you refocusing Takeda’s oncology strategy?

DR. PK MORROW: We’ve taken some strategic pivots. I came to Takeda inspired by the legacy of multiple myeloma, which we had developed amazing therapies for, including Velcade and Ninlaro. Now the landscape has significantly changed, with multiple therapies being approved. I realized we needed to pivot and address the evolving disease landscape. We need to address the diseases that have the greatest unmet need.

We determined that, for example, we were going to pivot from … development of myeloma agents to development of therapies in the leukemias for hematology. Now we’ve moved toward ALL [acute lymphoblastic leukemia] and we’re developing ponatinib.

We also have an option agreement with Ascentage [Pharma] to potentially develop a therapy called olverembatinib. We saw that patients with [chronic myeloid leukemia] were developing T315I mutations along the course of their disease as they were being treated for CML with first- and second-generation tyrosine kinase inhibitors. We looked at that and said: Where can we address the greatest unmet need?

What will this new strategy look like?

We want to be laser focused on the unmet need, so we’re really going to be focused on three disease states: thoracic tumors, GI cancers and specific hematologic malignancies. We want to leverage our expertise and our current existing platforms, so we’re going to focus on four modalities: ADCs [antibody-drug conjugates], bispecifics, small molecules and cell therapies.

Will we be opportunistic? Absolutely. If we see an amazingly exciting technology that has the ability to deliver in the short term and intermediate term for patients, we will strongly consider that. But we wanted to have a strong, three-by-four paradigm to start with that enabled us to look at business development opportunities and our internal pipeline in a robust, scientific and strategic framework.

What are your longer-term goals?

For the intermediate and long term, my goal — and the reason I came here — is to make a truly global impact in terms of bringing impactful therapies to patients as rapidly as possible. I know from practicing at MD Anderson that patients are waiting. Cancer is so aggressive that we cannot let a day go by without advancing these programs. Hopefully [in a year] I’ll be able to tell you that we’re truly delivering on this “four modality, three disease state” strategy for patients

A long development road has paid off for Iovance Biotherapeutics, which won an accelerated approval for the first cell therapy to treat advanced melanoma. The FDA OK will also swing the door open to a promising type of immunotherapy for solid tumors. 

Iovance’s Amtagvi uses tumor-infiltrating lymphocytes (TIL) immune cells taken directly from the tumor and fortifies them to fight cancer. 

Academic researchers have studied TIL therapy for decades, but scientific and regulatory factors slowed the path to commercialization, said Jason Bock, co-founder and CEO of the Cell Therapy Manufacturing Center (CTMC), and an expert on TIL therapy. 

“This is the first cell therapy modality that has shown good results in solid tumors,” he said. 

While CAR T-cell therapies have been game-changing in blood cancers, they have largely fallen flat in solid tumors, which comprise about 90% of cancers, he said. TIL therapy is a one-time treatment with the potential to cure solid tumors — some treated patients have been cancer-free for a decade or more, Bock said.

 

Amtagvi will cost approximately $515,00 per patent before insurance and discounts. The FDA signed off on the therapy based on its phase 2 results, but Iovance is following up with a phase 3 confirmatory trial, which will include patients with melanoma that can’t be surgically removed, has spread to other parts of the body or was previously treated with a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor. 

While Amtagvi will give hope to patients with no other treatment options, it may also make even better treatments possible. 

“It will blaze this trail for others to follow on with enhanced next-generation products. I think those will be where we really see some dramatic impacts of TIL in the overall treatment of solid tumors,” Bock said.

Harnessing the immune system

Patients receive Amtagvi in authorized treatment centers where TILs are extracted and expanded using a proprietary process that takes around 22 days. The patient then undergoes lymphodepletion to kill existing T cells before doctors infuse them with billions of beefed-up cells, accompanied by a short course of high-dose Proleukin, an interleukin-2 (IL-2) product Iovance acquired in 2023 from Clinigen Limited. The IL-2 helps the infused cells transition from the controlled lab environment into the body, Bock said. 

Treatment can result in low blood counts, infection and other organ-related complications that can be serious — risks the FDA highlighted in a black box warning. The accompanying IL-2 regimen can bring its own risks, too. 

“The issue with high-dose IL-2 is that it carries its own toxicities and is a difficult treatment for patients to handle,” Bock said. 

Companies developing next-generation TIL treatments are working on alternatives to IL-2, which could reduce potential side effects. The lymphodepletion process may also be problematic. In December, the FDA placed a clinical hold on an Iovance lung cancer trial after a patient died, potentially related to this process.  

A difficult development road 

One reason it took so long to bring a TIL treatment to market is due to one of its cancer-fighting strengths, Bock said. Unlike CAR-T cells, which have to be engineered, the body naturally deploys TILs to infiltrate a tumor’s layers to fight the cancer. The challenge is that TIL cells can get “beaten down” in the process, Bock said, and the tumor evolves to avoid or repress them. 

“They don’t have the fortitude to contain the cancer. So, the goal [with TIL therapies] is to enhance and multiply them to turn them into an army capable of a successful attack,” Bock said.

TILs are also polyclonal and can recognize many targets on cancer cells. But while that makes them alluring as a therapeutic, it also created regulatory hurdles and the FDA had to hammer out a way to regulate this new kind of drug without a predefined target, Bock said.

TILs in the pipeline 

Several other TIL treatments are currently in the pipeline, and many also target melanoma, Bock said. But in theory, TILs have the potential to work against a broad range of solid tumor types. For the next generation to be effective in other cancers, better manufacturing methods will be needed to fortify TILs for battle, Bock said. 

While much of the work on TILs still happens in academic research centers, several companies, such as Turnstone Biologics, Lyell and Instil Bio are testing second-generation TILs, and assessing the modality against targets including breast, colorectal and ovarian cancer. Iovance is also targeting cervical cancer, non-small cell lung cancer, and head and neck squamous cell carcinoma.

Now that the FDA has approved Amtagvi, Bock predicts investment in TILs will surge, much like it did when the FDA approved the first CAR-T cell treatment. 

“It's hard to be the first, but what's exciting is that after you're done with the first there's a trail there for others to build upon and improve upon,” Bock said.