NEW YORK – In February, cell therapy developers, researchers, and oncologists celebrated Iovance Biotherapeutics’ Amtagvi (lifileucel) US approval in advanced melanoma. As the first autologous cell therapy to win authorization in a solid tumor setting, its path to market could be a model for others to follow.
“Finally, we got an adopted cell therapy for a solid tumor,” Kai He, an oncologist at Ohio State University Comprehensive Cancer Center, said of the US Food and Drug Administration’s Feb. 16 approval of Amtagvi. “It’s very encouraging as a physician.”
With the regulatory cloud lifted, drugmakers and physician scientists are energized to address the myriad mechanistic and logistical issues challenging cell therapy development in solid tumors. In the months since, drugmakers and researchers developing all manner of cell therapies, tumor infiltrating lymphocytes (TILs) like Amtagvi, chimeric antigen receptors (CARs), and T-cell receptors (TCRs) have wasted no time moving ahead with solid tumor cell therapy plans. He has seen medical centers working to implement cell therapies in solid tumors at a faster pace than before. “I’ve seen more and more startups and established companies moving into this area of the field,” he added.
Indeed, according to oncologists, researchers, and drugmakers with cell therapies in early- and late-stage development, the Amtagvi approval has had a galvanizing effect. If Iovance could navigate a bespoke, living TIL therapy through the FDA, they, too, had a shot at commercial success.
“For years, the holdup at the [biologics license application]-level cast a cloud over the field because of the presence of regulatory uncertainty,” said Micah Benson, CSO of KSQ Therapeutics, a cell therapy company developing its own TIL approach. Due to the lack of established frameworks for bringing this type of therapy to market, it took Iovance several years to get the FDA to accept its BLA for Amtagvi in advanced melanoma.
Now, Benson said, “Iovance has pioneered what the regulatory path would look like. From what they’ve been able to accomplish, others in the field can apply lessons learned to their own regulatory paths.”
Even with the benefit of Iovance’s regulatory experience, however, drugmakers developing cell therapies for solid tumors still have a lot to figure out. Researchers, for example, are grappling with how to improve upon this first-generation TIL therapy so the next iteration of agents benefit more patients with fewer toxicities. And beyond the TIL therapy space, drugmakers that have successfully designed CAR T cells for treating blood cancers are still wrestling with how to make the CAR construct work in solid tumors.
Drugmakers’ face multiple challenges when it comes to treating solid tumors with cell therapies. They must first select the right tumor target and get around that target’s heterogeneity. Then, they must ensure the patient’s immune cells don’t become exhausted once infused and minimize the toxicities of co-administered chemotherapy and interleukin 2 (IL2). And, ultimately, drug sponsors must find a logistically feasible way to manufacture these bespoke therapies at scale and get them back into patients’ bodies as quickly as possible.
Choosing a target
According to Michael Lotze, a professor of surgery, immunology, and bioengineering at the University of Pittsburgh School of Medicine, CAR T-cell therapy’s lack of success in solid tumors boils down to the difficulty of identifying the right target antigen.
Autologous CAR T-cell therapies for leukemias, lymphomas, and multiple myeloma go after tumor surface targets like CD19 and the B-cell maturation antigen (BCMA), which are reliably expressed on cancer cells. “We recognize now that CD19 and BCMA are targets that are not unique to the cancer, but are unique to B cells,” said Elliot Norry, chief medical officer at the Philadelphia-based cell therapy company Adaptimmune. “And when you use one of those therapies, you can also affect the noncancerous B-cell population.”
This has an on-target, off-tumor effect, in which the patient’s engineered T cells attack healthy cells that express the same target as the cancer cells. “But it turns out that you can live pretty well without the vast majority, if not all, of your B cells,” Norry said.
Over time, many of these patients do need to have their immune competency managed, but otherwise, Norry said, the destruction of the healthy B cells is not catastrophic. “Generally, they do okay,” he said.
In solid tumors, though, attacking healthy tissues expressing the target is not a viable strategy. “If you were to tell me I could attack a lung cancer but I’m also going to knock out most of the lung tissue … that’s not going to be a successful therapy,” he said.
Unfortunately, for CAR T-cell therapy, most of the known targets that engineered T cells could theoretically go after are not exclusive to cancer tissue. These antigens may be expressed in excess in the cancer tissue, but their presence on normal cells means that therapies designed to home in on them will cause patients unacceptable toxicity.
Norry’s company, Adaptimmune, is trying to get around this challenge with an autologous TCR T-cell therapy. Having recently filed a BLA with the FDA for its lead candidate afamitresgene autoleucel (afami-cel), the firm may be the furthest on the path to getting the next autologous cell therapy on the market in a solid tumor setting, in this case advanced synovial sarcoma. The FDA is expected to decide on Adaptimmune’s BLA by Aug. 4.
Adaptimmune is trying to overcome the target issue by going after major histocompatibility complex (MHC) peptides on solid tumor cells with its patient-specific TCR T-cell therapy. Instead of directly targeting cell surface antigens, Adaptimmune is going after the molecules responsible for presenting tumor antigens to T cells for recognition. “The T-cell receptor recognizes that peptide HLA surface rather than a protein that’s just sitting on the cell surface,” Norry said. “It’s a very specific lock and key, and a T-cell receptor has to be very specific to that MHC complex.”
Adaptimmune’s engineered adoptive T cells, dubbed Specific Peptide Enhanced Affinity Receptors, or SPEARs, are harvested from patients, then engineered ex vivo to target the specific peptide MHC on the cell surface, MAGE-A4 in afami-cel’s case. The T cells are then able to recognize, target, and kill the tumor cells.
The mechanism is similar to a TIL therapy like Amtagvi, Norry explained, only Amtagvi involves taking out T cells from a solid tumor sample that have already trafficked into the tumor and can therefore already recognize it. The tumor-infiltrating lymphocytes comprising Amtagvi are expanded outside the patient’s body before they’re reinfused, but they don’t involve any engineering or selection like Adaptimmune’s SPEAR T cells do.
In Norry’s view, TCR T-cell and TIL therapies both have their advantages and specific uses. “[Both types of] therapies will have a very storied future, and we are rooting for our neighbors over at Iovance,” he said.
One of the advantages of TCR therapies is that while TIL therapies are particularly efficacious against immunogenic tumors like melanoma or non-small cell lung cancer, engineered TCR therapies appear to work in less immunogenic, cold tumors, like synovial sarcoma.
“Melanoma has a high mutational burden, and it’s well known that T cells regularly traffic into melanomas,” Norry said. “The TILs are going to be more naturally amendable to treating that type of tumor.” The ability of the engineered SPEAR T cells to traffic into less naturally immunogenic tumors may give them a leg up over TIL therapy in certain indications, he suggested.
The clinical dataset that Adaptimmune submitted to the FDA for afami-cel includes results from one of the cohorts in the pivotal Phase II SPEARHEAD-1 clinical trial, in which 39 percent of advanced, MAGE-A4-positive synovial sarcoma patients responded to afami-cel. The median duration of response was 12 months, and the median overall survival was 17 months. Two years after treatment, 70 percent of patients treated with afami-cel were still alive.
Despite certain advantages, TCR T-cell therapies also have their share of challenges. For instance, the treatments require patients to have a specific HLA type, which limits the eligible patient population.
“The HLA type is actually essential to the efficacy and safety of afami-cel, and TCR T cells in general,” Norry said. Peptide MHC complexes are HLA specific, meaning a treatment like afami-cel wouldn’t be able to recognize the intended peptide MHC in patients with different HLA types. The HLA type that patients must have to be eligible for afami-cel, HLA-A*02, is the most common HLA type in the Western world, occurring in 40 percent to 45 percent of the population.
According to Norry, Adaptimmune is conducting preclinical work looking for a peptide MHC for MAGE-A4 for patients with other HLA types. There are hundreds of HLA types in the global population, but Norry said his firm believes that if they can engineer their therapy for four different HLA types, it can reach up to 80 percent of the world’s population.
“It is our absolute desire to move beyond just HLA-A*02,” he said.
Beyond afami-cel, Adaptimmune is advancing another autologous TCR T-cell therapy, letetresgene autoleucel (lete-cel), toward a regulatory filing. This therapy, which GlaxoSmithKline previously licensed but then returned to Adaptimmune, is designed to target NY-ESO-1 as opposed to MAGE-A4. During the American Society of Clinical Oncology’s annual meeting this year, Adaptimmune will present interim data from a cohort of 45 synovial sarcoma and myxoid/round cell liposarcoma patients treated with lete-cel in the Phase II IGNYTE-ESO trial.
Grappling with heterogeneity
When it comes to homing in on an effective target for solid tumor cell therapy, the issue of target heterogeneity is cited just as often as the challenge of finding a target in the first place. “Every patient has a very different pattern of tumor antigens,” KSQ’s Benson said. “And you want to hit multiple antigens rather than just one.”
This, too, is part of the attraction of TIL therapy: Lymphocytes that have already infiltrated a patient’s tumor are going after multiple targets specific to that tumor. But the downside, again, is TIL therapy’s limited activity in heterogeneous tumors that aren’t as immunogenic.
At Massachusetts General Hospital, for instance, a group of researchers has been testing out a new type of CAR T-cell therapy in patients with glioblastoma. The therapy, dubbed CARv3-TEAM-E, involves autologous immune cells that are engineered to express a CAR that targets EGFR variant III. At the same time, the therapy is designed to secrete a molecule called TEAM — short for T-cell engaging antibody molecule — that targets wild-type EGFR.
The treatment was designed to go after both the mutated and wild-type EGFR to account for cellular heterogeneity in glioblastomas, wherein some tumor cells may express the EGFR variant and others may not. Though it’s still early days for this program, in March, Mass General researchers reported that three patients on a safety run-in portion of a Phase I trial had dramatic tumor regressions after receiving the autologous CARv3-TEAM-E cells.
BrainChild Bio is also trying to overcome target heterogeneity with its pipeline of autologous CAR T-cell therapies that go after four tumor antigens: B7-H3, EGFR806 HER2, and IL13-zetakine. The Seattle Children’s Hospital spinout is studying an adoptive cell therapy, dubbed SC-CAR4BRAIN, in a Phase I trial involving patients with diffuse intrinsic pontine glioma tumors. Eventually, BrainChild hopes its treatment will prove beneficial against all central nervous system tumors.
According to Lotze, the availability of CRISPR-Cas9 gene editing technologies could bolster cell therapy developers’ ability to select the best target and get around the heterogeneity challenge in solid tumors.
“To take 20,000 genes in the human genome, or even the 100 most interesting ones, and test them [as targets] in a stepwise fashion, would take you centuries,” he said. Instead, in the future, drugmakers could leverage gene editing to intentionally introduce heterogeneity into a cell therapy product and evaluate multiple cells against multiple targets in one trial.
A meeting earlier this month, hosted by the nonprofit Friends of Cancer Research (FOCR) and the Parker Institute for Cancer Immunotherapy, featured discussions on how CRISPR screens can be harnessed for developing next-generation cell and gene therapies. Marcela Maus, director of Mass General’s Cellular Immunotherapy Program and one of the researchers spearheading the CAR-TEAM approach, put forth the theoretical possibility of a single dose of autologous T cells transduced with a single antigen receptor with a known target specificity, to which a library of secondary modifications could be added using CRISPR.
The patient would undergo serial blood sampling and potentially tumor biopsies to quantify how many cells with each different gene edit are present in the tumor and in the blood over time. This, in turn, could allow researchers to identify the best secondary modifications and signatures that could be used for further drug development.
“The idea here is that, although each cell has the same specificity and the same binding receptor, they have one, or maybe two, gene knockouts to then [help us] understand the candidate genes that, when edited, confer a selective advantage to either trafficking or persistence in the patient,” Maus said at the meeting.
But drugmakers and regulators haven’t readily embraced CRISPR screens when designing cell therapies because, traditionally, drug development is a reductionist affair, Maus observed, where clinical trials measure how well a treatment interrogates a specific biological pathway involved in a disease. Using CRISPR screens to edit multiple genes and see which one improves a patient’s outcomes could introduce too many confounding variables. “But cellular products are always heterogeneous, whether they are gene modified or not,” Maus reflected.
“The strategy is scientifically doable,” Lotze said of the approach Maus described. “Now, the question is, will regulatory agencies allow it?” Part of the reason to bring together stakeholders and have these types of discussions, Lotze noted, is to get regulators and researchers aligned on the clinical trial design parameters and safety considerations for new treatment approaches like cell therapies.
Avoiding cell exhaustion
More drugmakers do seem willing to test out CRISPR gene editing as a tool to enhance their cell therapies’ persistence, another challenging aspect of advancing these agents in solid tumors. As T cells struggle to infiltrate a solid tumor — often due to the immunosuppressive environment surrounding the cancer — they can become exhausted and lose their efficacy.
Using gene editing to inactivate certain genes contributing to this exhaustion may be one solution. This is the idea behind KSQ’s CRISPR-Cas9-engineered TIL therapy platform that it dubs eTIL. KSQ’s lead product, KSQ-001EX, is an autologous TIL therapy engineered to inactivate the SOCS1 gene, in turn improving the T cells’ ability to infiltrate the tumor and expand once there.
With less risk of T-cell exhaustion, paired with enhanced tumor infiltration, the idea is that patients can receive a lower dose of the TILs and potentially less lymphodepleting chemotherapy and IL2 conditioning, Benson said. “One of the reasons why patients undergo lymphodepleting chemotherapy as well as receive high-dose IL2 [in autologous TIL therapy regimens] is that the transferred TIL are then subject to higher levels of cytokines that enhance their engraftment survival and differentiation,” he said. “What we’re trying to do is achieve essentially the same mechanism through different means. Rather than enhancing exogenously the amount of cytokines that TIL are subject to, we’re trying to take the brakes off of cytokine signaling intrinsic to the TIL.”
Recently, KSQ launched its Phase I safety lead-in trial of KSQ-001EX in patients with advanced melanoma, head and neck cancer, and NSCLC. Although for this trial, KSQ is including lymphodepleting chemotherapy as part of the autologous TIL regimen, Benson said the firm might be looking to eventually reduce or eliminate this step. As for IL2, the firm is starting off by removing this conditioning therapy from the equation, but Benson said there would be the option to add IL2 back in if necessary.
KSQ also has a TIL product in the works, KSQ-004EX, that’s engineered to knock out SOCS1 and another gene called Regnase-1. As KSQ advances KSQ-001EX and KSQ-004EX through studies, Benson acknowledged that therapies that are both bespoke and gene-edited may face unique regulatory hurdles. But at least now, KSQ’s products won’t be the first TIL therapies to navigate the regulatory process, nor will they be the first gene-edited therapies to do so.
“We’re sitting in a pretty interesting space where we can apply lessons learned from pioneers in the field to bring our own pioneering approach, a CRISPR-Cas9 gene-engineered TIL, through the approval process,” Bensen said.
When Casgevy (exagamglogene autotemcel) was approved for sickle cell disease late last year, it became the first CRISPR-Cas9 gene-edited therapy to enter the commercial market.
“Certainly, other players in the TIL field can apply lessons learned from what Iovance has been able to accomplish to their own regulatory path,” Benson said. “And since our TIL is gene-edited, we will certainly incorporate some lessons learned from the recent approval of CRISPR Therapeutics’ and Vertex’s Casgevy.”
Iovance is also working on developing a next iteration of its TIL product with a gene knockout. The firm’s engineered TIL candidate, IOV-4001, uses a gene-editing technology called TALEN, which Iovance licensed from Cellectis, to inactivate the gene coding for PD-1.
The firm is evaluating IOV-4001 in a Phase I trial for advanced melanoma and NSCLC.
Other firms, meanwhile, have been applying distinct approaches to cracking the problem of T-cell persistence. University of Pennsylvania spinout Verismo, for instance, is evaluating an autologous T-cell therapy dubbed SynKIR-110, in which ovarian cancer, mesothelioma, and cholangiocarcinoma patients’ immune cells are engineered to express a mesothelin-targeting receptor tied to an NK cell membrane anchor. This multichain structure on these engineered cells includes components from natural killer cells, which Verismo believes could help skirt T-cell terminal exhaustion.
Other firms have tried using natural killer cells, or other immune cells like macrophages, as their products’ starting material. During the recent American Society for Gene and Cell Therapy’s annual meeting, for instance, Chinese biotech Cure Genetics presented early data from a trial of its CAR-NKT therapy, CGC729, in patients with advanced clear-cell renal cell carcinoma. The therapy uses autologous natural killer T cells, which the firm believes have unique abilities to prolong the cell therapy’s expansion in vivo and better infiltrate solid tumors. Though the ASGCT data only included five patients, the firm reported that the safety profile was encouraging and that two out of four efficacy-evaluable patients had responded to the treatment.
Meanwhile, Carisma Therapeutics, a Philadelphia-based biotech, is using monocytes as the cell type for their autologous CAR therapy, CT-0525, and testing it in HER2-expressing solid tumors.
These approaches are just a few among myriad strategies drugmakers are trying out to home in on solid tumors with cell therapies that will, ideally, stay active against the cancer cells once they’re inside patients’ bodies.
And drugmakers, oncologists, and others in the field see these approaches as just the beginning in the new era of autologous cell therapy for solid tumors. Already, other firms are thinking outside the box with their approaches for directing patients’ T cells to their tumors and avoiding exhaustion. Philadelphia-based Imvax, for instance, is trying a unique glioblastoma cell therapy approach that involves harvesting a patients’ brain tumor, then inserting small pieces of tissue from that tumor inside of dime-sized diffusibility chambers. In a Phase II clinical trial, Imvax is temporarily implanting these chambers into patients’ abdomens then removing them. The idea is to train the patient’s immune system to recognize the tumor cells so that those immune cells can penetrate the blood-brain barrier and attack the tumor there.
Scaling back on conditioning
KSQ is not the only drugmaker hoping their therapies might eventually reduce or eliminate the need for conditioning therapy and high-dose IL2. These conditioning therapies are part of what make autologous TIL therapy effective once infused — the lymphodepleting chemotherapy clears the way for the infused T cells to target cancer cells while the high-dose IL2 helps the T cells expand in vivo. However, these therapies also carry the risk of significant toxicities and can be particularly difficult to tolerate for advanced, heavily pretreated patients like those with melanoma now eligible for Iovance’s Amtagvi.
Ohio State’s He, who was an investigator on Iovance’s trials evaluating Amtagvi in NSCLC, said the intensity of the preconditioning chemotherapy and IL2, especially after patients undergo surgical resection for the tumor tissue needed to make their TILs, can be challenging for patients.
“For metastatic lung cancer patients, the average age is older than melanoma patients [at diagnosis], and the patient population often has a history of smoking and underlying pulmonary and cardiac [conditions],” He said. “How they can tolerate the whole regimen can be a challenge.”
Phase II studies have shown the safety profile to be manageable for TIL therapy in NSCLC, He said. But given these toxicity risks, strategies to reduce the intensity of these regimens have been top of mind. For example, Obsidian Therapeutics is developing a modified version of its autologous TIL therapy, OBX-115, with its own, membrane-bound IL15. In early-phase trials for OBX-115, the Cambridge, Massachusetts-based firm is enrolling metastatic NSCLC and melanoma patients.
OBX-115 is genetically modified to produce membrane-bound IL15, eliminating the need for separate IL2 infusions. The membrane-bound IL15 can be “turned on” or “turned off” with a small molecule. At ASCO’s upcoming annual meeting, Obsidian will present data from a Phase I first-in-human study of OBX-115 in advanced melanoma patients who are resistant to checkpoint inhibitors.
High hopes for a point-of-care future
While there are promising signs that drugmakers are systematically working through the myriad drug design challenges of developing cell therapies in solid tumors, the logistics of bringing these treatments to patients remain a particularly intractable last-mile hurdle for all autologous cell therapies. Since CAR T-cell therapies first entered the market in 2017 for blood cancers, they have struggled to scale up production. Each patient’s cells must by frozen and shipped to a central facility for manufacturing then frozen and shipped back. The whole process takes weeks or months, depending on the therapy, and the potential hiccups in the manufacturing chain are numerous.
During a call to discuss first quarter financials earlier this month, Iovance interim President and CEO Fred Vogt said that Amtagvi’s initial commercial rollout has been positive, and that Iovance has been able to deliver the TIL therapy to patients within its target turnaround time of approximately 34 days. Even so, a month is a long time to wait for end-stage advanced cancer patients. Moreover, the requirement that patients must receive this treatment in a specialized center automatically limits patients’ access.
Ohio State has a 2,500-square-foot cell therapy manufacturing facility, making it possible to produce autologous cell therapies near where patients are receiving care. However, according to He, drugmakers will have to standardize the manufacturing process and figure out how to seamlessly transfer these highly specific, often proprietary manufacturing processes to new sites before the field can really start to move toward point-of-care delivery. “In theory it’s doable, but it’s still premature,” He said. “How are we going to implement this?”
It’s encouraging to University of Pittsburgh’s Lotze that during the FOCR meeting, Peter Marks, the director of the FDA’s Center for Biologics Evaluation and Research (CBER), was eager to discuss point-of-care cell therapy development, particularly which tests to develop to ensure a cell therapy product made in New York, for example, would be the same as one made in Houston or San Francisco.
“The way I see it, the major impediment to advancing cell and gene therapy is that the current protocols require an airplane in the beginning and an airplane at the end,” Lotze said. “If we could find a way of doing production closer to the patients, we would be much better off.”
