Investigators Aim Novel T-Cell Therapy at Solid Tumor Target

ADP-A2M4CD8, a novel T-cell therapy, is being investigated in a range of tumor types that express MAGEA4, an antigen expressed in solid tumors that investigators say represents a promising target for cellular immunotherapy.

The ongoing phase 1 SURPASS trial (NCT04044859), a first-in-human study, is open to patients with 8 cancer types, although investigators are focused on recruiting participants with gastroesophageal cancers, head and neck squamous cell carcinoma (HNSCC), and lung and bladder cancers.

Based on early positive data, investigators are planning a phase 2 trial in patients with gastroesophageal cancers.¹

ADP-A2M4CD8 is an autologous therapy directed toward the HLA complex/MAGEA4 antigen. The therapy is manufactured from the patient’s peripheral blood cells, which are harvested through leukapheresis and transduced with a lentiviral vector containing a MAGEA4 T-cell receptor (TCR) and expanded. Specific peptide-enhanced affinity receptor (SPEAR) technology is used to selectively engineer TCRs modified to enhance binding to cancer cells.^1,2

“The SPEAR T-cells are an interesting technology,” David S. Hong, MD, the lead investigator in the SURPASS trial, said in an interview with OncologyLive^®. “The SPEAR T-cells are CD4 and CD8α cells that have been reengineered to express a TCR that can bind to these HLA-restricted receptor and antigen complexes on cancer cells.”

MAGEA4, a cancer testis antigen, is broadly expressed in many solid tumor types.

In a study of 585 samples in 21 tumor types, investigators found that MAGEA4 was expressed in 36.6% of samples (range, 30.7%-37.%). The antigen was identified in 9 tumor types, including 54.9% of esophageal cancers, 37.5% of HNSCCs, and 35.0% of gastric cancers.³

Investigators are seeking a solid tumor target for T-cell therapies, said Hong, who is deputy chair of the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center in Houston.

So far, chimeric antigen receptor (CAR) T-cell therapies that bind to CD19 have succeeded in hematologic malignancies, with 4 FDA-approved products. “Thus far, we haven’t seen strong responses in treating solid tumors with available cellular therapies, in large part because antigens expressed are not restricted to the tumors,” Hong said in a news release.⁴

ADP-A2M4CD8 represents another step in the development of the MAGEA4targeting T-cell therapy. A previous version, called ADP-A2M4, showed activity in synovial sarcoma, Hong said, but investigators sought to improve its efficacy by adding SPEAR T cells that coexpress the CD8α receptor. “There was still a way to go with other tumor types, such as esophageal and head and neck and other cancers. Adding the CD8α coreceptors to the existing construct allows for greater cytotoxicity and enhances engagement across the wider immune system,” he said.

THE SURPASS TRIAL

In the SURPASS trial, investigators are seeking to recruit 30 patients. Although the focus is on gastroesophageal cancers, HNSCC, and lung and bladder cancers, enrollment also is open for patients with ovarian, melanoma, myxoid/round cell liposarcoma (MRCLS), or synovial sarcoma. Enrollment had been paused for several months because of the coronavirus disease 2019 (COVID-19) pandemic, but is now ongoing, Hong said.

“This is an in-patient trial, and the hospitals not only at MD Anderson but everywhere were worried they were going to get overwhelmed with COVID patients in the ICUs,” Hong said.

To be eligible for the trial, patients must have MAGEA4 expression of at least 2+in 30% or more of tumor cells on immunohistochemistry staining and test positive for at least 1 HLA-A*02 inclusion allele. Participants also must have received or refused standard antitumor regimens with no more than 3 lines of prior systemic therapy in the metastatic or unresectable locally advanced setting.¹

The study uses a modified 3+3 design, with up to 2 dose cohorts plus an expansion cohort (FIGURE).¹ After enrollment, patients undergo leukapheresis, and their white blood cells are sent to Adaptimmune Therapeutics, the developer of ADP-A2M4CD8, for engineering with SPEAR T cells. Four to 7 days before infusion, patients undergo lymphodepletion comprised of f ludarabine at 30 mg/m² daily for 4 days and cyclophosphamide at 600 mg/m² daily for 3 days.

After receiving the ADP-A2M4CD8 therapy, patients remain in the hospital for a minimum of 3 days and are discharged at the investigator’s discretion. Investigators will monitor patients until disease progression, withdrawal from the interventional phase of study, or death to assess for efficacy and safety. In the first year after infusion, investigations monitor and assess patients at months 3, 6, and 12. From years 2 to 5, investigators monitor patients every 6 months. After year 5, investigators assess patients annually for up to 15 years.

This is a complex trial to administer, Hong said. “We have to determine the timing for the leukapheresis and the timing for the dose-escalation trial, as well as the timing for the lymphodepletion. We have to determine insurance clearance, etc,” he said.

The trial is being conducted in 17 sites in the United States, Canada, and Spain.

INITIAL FINDINGS FROM SURPASS

Hong and colleagues presented data during the Society for Immunotherapy of Cancer’s annual meeting in November 2020 demonstrating early efficacy signals and a manageable safety profile for ADP-A2M4CD8. Among 6 patients with heavily pretreated advanced cancers, 3 were treated with target doses of 1 billion SPEAR T cells and 3 received target doses of 5 billion SPEAR T cells.¹

Initial responses appear promising and have the potential to offer long-term benef it for patients in this space, Hong said. Notably, 5 out of 6 patients experienced initial tumor shrinkage following T-cell infusion. There were 2 confirmed partial responses (PRs)—in 1 patient with esophagogastric junction cancer ADP-A2M4CD8 is an autologous T-cell therapy directed at the HLA complex/ MAGEA4 antigen. (EJC) and 1 with HNSCC. The other 4 patients had stable disease; these included 1 each with MRCLS, esophageal, ovarian cancer, and EJC.¹

In terms of safety, 3 patients experienced adverse effects (AEs) of grade 3 or more, including lymphopenia, neutropenia, and anemia. For any-grade AEs, 4 patients experienced cytokine release syndrome (CRS) and 3 had fatigue.¹

“What’s interesting is that we don’t see the level and the percentage of cytokine release syndrome that you would see with CAR T therapy,” Hong said. “The most common adverse effects have been associated with the lymphodepletion, such as neutropenia or lymphopenia. The vast majority of these patients had mild symptoms of CRS. Some had mild fever. Some had some mild fatigue.”

Preclinical data presented at the 2019 American Association for Cancer Research annual meeting found that ADP-A2M4CD8 increased T-cell activation and improved engagement with the immune system in dendritic cells and T-cells cocultured with MAGEA4–positive cancer cell lines There was no additional off-target reactivity in vitro. This was a proof-of-concept study that focused on CD4+ T-cell function using in vitro assays.⁴

Adaptimmune plans to launch SURPASS-2, a phase 2 trial of ADP-A2M4CD8 in gastroesophageal cancers, during the first half of 2021. The company expects to file a biologics license application for ADP-A2M4CD8 in gastroesophageal cancers in 2024.⁵

Meanwhile, investigators continue to evaluate ADP-A2M4 in the phase 2 SPEARHEAD 1 trial (NCT04044768) in patients with advanced synovial sarcoma or MRCLS. The registrational study is projected to complete enrollment in the first quarter of 2021.

Additionally, ADP-A2M4 is being studied in combination with pembrolizumab (Keytruda) in a pilot phase 2 trial, SPEARHEAD 2 trial (NCT04408898), in patients with recurrent or metastatic head and neck cancer.

Updated findings from a phase 1 trial of ADP-A2M4 in patients with synovial sarcoma who are MAGEA4 positive found that 7 of 16 patients (44%) had confirmed PRs per RECIST criteria, with disease control in 15 patients (94%). There was a median duration of response of 28 weeks (range, 12-72+), with 2 PRs that were ongoing beyond 72 weeks; and 11 of the 16 patients were alive at the time of data cutoff on September 1, 2020.⁶

References

1. Hong D, Clarke J, Johanns T, et al. Initial safety, efficacy, product attributes from the SURPASS trial with ADP-A2M4CD8, a SPEAR T-cell therapy incorporating an affinity optimized TCR targeting MAGE-A4 and a CD8α co-receptor. J Immunother Cancer. 2020;8(suppl 3):A231. doi:10.1136/jitc-2020SITC2020.0379
2. Hong DS, Van Tine BA, Olszanski AJ, et al. Phase I dose escalation and expansion trial to assess the safety and efficacy of ADP-A2M4 SPEAR T cells in advanced solid tumors. J Clin Oncol. 2020;38(suppl 15):102. doi:10.1200/JCO.2020.38.15_ suppl.102
3. Ishihara M, Kageyama S, Miyahara Y, et al. MAGE-A4, NYESO-1 and SAGE mRNA expression rates and co-expression relationships in solid tumours. BMC Cancer. 2020;20(1):606. doi:10.1186/s12885-020-07098-4.
4. Anderson VE, Weber AM, Wiedermann, et al. Enhanced activity of second-generation MAGE-A4 SPEAR T-cells through co-expression of a CD8α homodimer. Cancer Res. 2019;79(suppl 13):2313. doi:10.1158/1538-7445.AM2019-2313
5. Adaptimmune to showcase market potential for SPEAR T-cell portfolio and pipeline with multiple cell therapy platforms during virtual investor day. News release. Adaptimmune. November 20, 2020. Accessed January 21, 2021. http://bit.ly/3qRR00C
6. Durable responses with ADP-A2M4 in synovial sarcoma with confirmed responses in 44% of patients and disease control rate of 94% presented at CTOS. News release. Adaptimmune. November 19, 2020. Accessed January 25, 2021. ht tp://bit. ly/3sW5ui0