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Immatics Advancing T-Cell Receptor Therapies for Solid Cancers at European, US Study Sites

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NEW YORK – Clinical-stage biopharmaceutical company Immatics earlier this month announced that the first patient in Europe had been treated with its proprietary adoptive cell therapy, dubbed IMA202.

The patient was treated in Germany after receiving the go ahead from the Paul Ehrlich Institute, Germany's regulatory body responsible for cell and gene therapies. This marked the European expansion of Immatics' clinical trial for IMA202, a T-cell receptor (TCR)-based immunotherapy that is already being studied at trial sites in the US in solid tumors that express MAGEA1. IMA202 is developed within Immatics' ACTengine program, which has produced two other adoptive cell therapies undergoing early-phase clinical trials; a third is in preclinical studies.

Adoptive cell therapy, in which patients' T cells or other immune cells are harvested from their body, genetically engineered with receptors that bind to target proteins on cancer cells, and infused back into the body to attack those cancer cells, isn't a new technology. Three CAR T-cell therapies in recent years have been approved in the US, including tisagenlecleucel (Novartis' Kymriah), axicabtagene ciloleucel (Gilead's Yescarta), and brexucabtagene autoleucel (Gilead/Kite's Tecartus). Countless other iterations of the approach are currently in various stages of clinical trials.

"Cell therapy is the fastest growing sub-subspecialty within immuno-oncology," said Cedrik Britten, who joined Immatics as chief medical officer this June. "It's a very vibrant space with lots of money and lots of hope and very fast technology and innovation cycles."

But to date, the successes of these cell therapies, for the most part, have been in hematologic malignancies and lymphomas, with CAR T-cell therapies that bind to CD19 demonstrating the most benefit. Adoptive cell therapies for solid cancers have proven more challenging to develop, but according to Britten, that's exactly why Immatics is focusing on this space.

"We are primarily focused on solid cancers because we think that it's the biggest area of unmet medical need," he explained. "And it's also the biggest opportunity to win."

Selecting 'true targets'

Immatics, based in Houston and Tuebingen, Germany, was first listed on the NASDAQ in July after combining its business with Arya Sciences Acquisition Corp. The company, which is also working to develop off-the-shelf cell therapies in addition to its ACTengine program, wants to differentiate itself in the cell therapy space through the selection of what it calls "true cancer targets." The receptors that Immatics engineers onto patients' T cells are directed at specific protein peptides that are commonly expressed on HLA molecules in solid tumor cells but are rarely, if ever, expressed on healthy cells.

Immatics was already positioned to find and select these targets — which currently include peptides from MAGEA1, MAGAE4/8, PRAME, COL6A3 — in part because the company started off as a target engine long before it became a clinical-stage operation. Through years spent collecting and analyzing thousands of healthy tissue and tumor samples with mass spectrometry and counting and quantifying peptides, Britten explained, the company homed in on over 200 unique targets, of which the company is currently evaluating a select handful in preclinical and early-stage clinical trials.

The company's ultimate goal is to develop and validate adoptive cell therapies for a wide array of targets, allowing patients with solid tumors a high likelihood of matching to one of the available therapies. Other companies, Britten noted, have certainly chosen MAGEA1 and PRAME as targets due to their common expression on solid cancers. But what makes Immatics' targets "true targets" in his view is not the selection of the proteins themselves, but rather the peptides that the firm selects from within these proteins.

"From every single protein, there are lots of peptides that can be processed and presented and become targets," Britten said. "We find multiple of these peptides from our target proteins and what we do is we pick the one that has the highest copy number on the cell surface."

Immatics is betting that its method of identifying target peptides will result in a cell therapy with greater immune activity against solid tumors than treatments being developed by competitors, but only a clinical trial will be able to confirm that. Still, Britten highlighted the methods used to select these targets as a differentiator. Other companies, he said, often turn to predictive algorithms to select targets for cell therapies, whereas Immatics has used mass spectrometry to individually count and quantify the peptides. The proprietary mass spectrometry-based technologies that Immatics uses to identify their targets and corresponding T-cell receptors are called XPRESIDENT and XCEPTOR, respectively.

According to Britten, the mass spectrometry approach requires immense time and resources but the investment may pay off in the end. A 2018 paper in the journal Proteomics on Immatics' personalized target selection reads, "While the significant cost and the labor‐intensive nature of direct immunopeptidome analysis by mass spectrometry represent a substantial barrier, the information gained by this approach may ultimately prove invaluable and may enable — besides direct target identification — the further improvement of predictive approaches."

ACTengine process, ongoing trials

Over the years, the company has generated a large database with information about these target peptides that it can now draw on for its drug development efforts. Out of the hundreds of peptides in that database, three are currently being evaluated with the company's T-cell receptor-based therapies in Phase I clinical trials.

The therapies targeting these peptides, called IMA201, IMA202, and IMA203, are being evaluated in basket trials, which are respectively enrolling patients with metastatic solid tumors who express the specific MAGEA4/8, MAGEA1, and PRAME targets. A fourth product, IMA204, which targets COL6A3, is currently being evaluated in preclinical studies. Preliminary results and safety profiles are not yet public, though the company plans to reveal them in early 2021.

The multi-cohort basket design of the clinical trials facilitates the enrollment of patients with various types of solid tumors who express the corresponding target. The primary outcomes assessed in the trials are centered around safety and tolerability, though the company will also assess secondary endpoints including the persistence of the T cells and observed tumor shrinkage. For the IMA203 trial, a subgroup of patients will receive atezolizumab (Genentech's Tecentriq) in addition to the adoptive cell therapy.

To screen patients for enrollment, Immatics uses its PCR-based test, called IMAdetect, to determine if patients' tumors express the target peptides to a level consistent with pre-set thresholds of positivity. Typically, the screening test takes three to five days after the collection of a patient's biopsy. Based on a positive test, a patient may be eligible to receive the TCR-based therapy for their specific target.

Britten highlighted that patients are screened for all three targets for Immatics' ongoing basket trials, so if they are negative for MAGEA1, their sample would then be tested for PRAME and MAGEA4/8 to assess if they might be eligible for one of the other trials instead.

"We have a very low screening failure rate and a very efficient method to find patients," he said, adding that investigators are encouraged to screen patients with cancer types that are more likely to express these targets, such as melanoma, as opposed to colorectal cancer and mesothelioma, which tend not to express these target antigens.

Manufacturing processes, partnerships

Currently, Immatics engineers patients' T cells in Houston, at University of Texas Health Sciences Center's manufacturing facility. In early August, the company announced that it had extended its collaboration with UTHealth, ensuring exclusive access to the facilities until the end of 2024. Immatics' manufacturing personnel are responsible for the T-cell production — during which patients' cells are engineered with the proper receptors for their targets — and are supported by a UTHealth-Immatics joint team. Immatics anticipates that the UTHealth location has the capacity to manufacture up to 48 T-cell products per month.

Britten did not disclose how many patients have been enrolled and received treatments within the company's various studies so far. However, the nature of adoptive cell therapy is such that patients receive a one-time treatment. So, it is feasible that the facility will have the capacity to manufacture treatments for the 15 patients expected to be enrolled for the IMA201 study, the 15 patients estimated to receive IMA202, and the 33 patients estimated to partake in the IMA203 study over four years.

Expanding manufacturing sites is a long-term priority for the company and will be necessary given the European expansion of its drug trials. In addition to the IMA202 trial, the Paul Ehrlich Institute also granted approval for Immatics to commence its IMA203 clinical trial in Germany, and as of now, patients' white blood cells are frozen and shipped from locations as far as Germany to the Texas manufacturing location, where they are engineered and then shipped back to the patient's location.

"Obviously, if we have a large pipeline of patients in Europe, the question of whether we want to manufacture centrally or locally or globally is something we have to answer," Britten said. "We will make sure that the manufacturing footprint at all stages will be in harmony with the clinical footprint and the success of the pipeline."