Chimeric antigen receptor T-cell therapies have shown remarkable efficacy in leukemia and lymphoma patients who relapsed or were refractory to several prior treatments, but many challenges remain in the cancer cell therapy field. Strategies that may improve upon first-generation therapies were presented during the American Association for Cancer Research virtual meeting with encouraging early activity, but these treatments also have hurdles to overcome.
Data from the first patients treated with novel cell therapy constructs and combinations from Gracell Biotechnologies Co. Ltd., Iovance Biotherapeutics Inc., Gilead Sciences Inc. (NASDAQ: [[ticker:GILD]]) and the US National Cancer Institute were presented on 28 April during AACR’s plenary session on adoptive cell transfer therapy. The AACR meeting was changed from a 24-29 April convention in San Diego to an online event scheduled for 27-28 April and 22-24 June due to the COVID-19 pandemic.
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These next-generation approaches attempt to address issues such as CAR-T cell persistence, loss of response due to antigen escape, the lack of T-cell therapies for solid tumors and the weeks-long manufacturing required for autologous products. (Also see “Next-Generation CAR-Ts Tackle First-Generation Safety, Solid Tumor Challenges” – Scrip, 21 Apr, 2018.)
GRACELL’S ALLOGENEIC CAR-T HAS NOVEL TARGET
The first two CAR-T therapies approved globally – Gilead subsidiary Kite Pharma Inc.’s Yescarta (axicabtagene ciloleucel) and Novartis AG’s(NYSE: [[ticker:NVS]]) Kymriah (tisagenlecleucel)—are autologous therapies requiring extraction of patients’ own T-cells, which the companies reengineer to target CD19 before the cells are expanded and infused back into patients.
Allogeneic products, like Gracell’s GC027, use healthy donor cells so that CAR-T therapies can be manufactured as off-the-shelf medicines for on-demand treatment. GC027 is being tested in relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia (T-ALL), which affects about 20 percent to 25 percent of adult ALL patients and 12 percent to 15 percent of pediatric ALL patients. The standard of care for T-ALL is multi-agent chemotherapy and most patients progress within two years.
Kymriah is approved in the US to treat pediatric and young adult patients with R/R B-cell ALL and adults with R/R large B-cell lymphoma; Yescarta also is approved for R/R large B-cell lymphoma. Both products take about two weeks to manufacture after T-cells are withdrawn from patients, which is enough time for blood cancers to progress so much that patients are no longer good candidates for CAR-T therapy.
GC027 targets CD7, an antigen present in about 95 percent of T-ALL. Gracell engineered the allogeneic CAR-T therapy with its TruUCAR technology platform, knocking out the donor cells’ T-cell receptor (TCR) to prevent graft-versus-host disease (GvHD) associated with the donor cells; CD7 also was knocked out of the engineered T-cells so the CAR-T cells wouldn’t attack each other – a process known as fratricide. (Also see “Regulatory Blessings Helping China CAR-Ts March Closer To Global Cancer Patients?” – Pink Sheet, 12 Dec, 2019.)
Suzhou- and Shanghai-based Gracell’s Xinxin Wang presented the findings from five T-ALL patients treated with three different doses of GC027—one-time infusions of 8 million, 10 million or 15 million cells. All patients achieved complete remission with or without complete blood count recovery (CR/CRi), including four (80 percent) who were minimal residual disease (MRD)-negative. Two patients have since relapsed, however.
Wang noted that there doesn’t seem to be a relationship between tumor burden and CAR-T cell expansion with GC027. But in terms of cell expansion and efficacy, she said a patient who responded at day 14 and relapsed at day 29 had the least CAR-T cell expansion of the five patients in the study.
The GC027 cells took about 10-14 days to expand in the treated patients and persisted for about three weeks, which Wang said was enough time to eliminate T-ALL cells and put patients into remission. Longer persistence could lead to infections, she added.
No GvHD or neurotoxicity was observed, but all GC027-treated patients experienced cytokine release syndrome (CRS). Neurotoxicity and CRS are common side effects with CAR-T therapies and can be severe, even deadly. Four patients treated with GC027 had grade 3 CRS and one had grade 4 CRS.
Wang noted that the aggressive lymphodepleting chemotherapy regimen given to patients before treatment with GC027 to make room for the reengineered T-cells may have contributed to the high rate and severity of CRS events.
Yvonne Chen from the David Geffen School of Medicine at the University of California, Los Angeles (UCLA), as the discussant for the GC027 data presentation, said the high doses Gracell tested also may have contributed to high CRS rates. However, she also said the absence of GvHD and neurotoxicity with GC027 was impressive.
Chen noted that highly engineered CAR-T cell technology platforms require a delicate balancing act. As more genetic alterations are made to knock out certain elements to improve persistence and function, she said there could be more impacts to CAR-T cell stability and uniformity.
IOVANCE’S TILs SHOW EFFICACY IN ADVANCED LUNG CANCER
Iovance has shown that its autologous tumor-infiltrating lymphocyte (TIL) technology is able to effectively treat advanced relapsed and refractory solid tumors with impressive response rates in early clinical testing for melanoma and cervical cancer. The company anticipates filing its lead TIL candidate lifileucel with the US Food and Drug Administration for approval to treat melanoma in 2020, making it the most advanced T-cell therapy technology in the clinic.
TILs are extracted from patients’ tumors, expanded ex vivo and then reengineered to evade the tumor’s immuno-suppressive environment and boost TIL replication and activation. Like CAR-T therapies, the TIL therapy is delivered back to the patient in a one-time infusion. The technology’s efficacy in solid tumors spurred talk of a potential Iovance acquisition earlier this year. (Also see “Iovance TIL Appeal Seen Luring Potential Buyers” – Scrip, 26 Feb, 2020.)
Data from a Phase I clinical trial in non-small cell lung cancer, which was conducted by investigators at H. Lee Moffitt Cancer Center in Tampa, FL for TIL candidate LN-145, were presented at AACR by Moffit’s Ben Creelan. This study, which was supported by Iovance and a Stand Up To Cancer Catalyst Grant, justified initiation of two NSCLC cohorts in the company’s basket trial known as IOV-COM-202. LN-145 is being tested in the Phase II Iovance-sponsored study as a monotherapy and in combination with Merck & Co. Inc.’s PD-1 inhibitor Keytruda (pembrolizumab).
Metastatic NSCLC patients in Moffit’s Phase I study received four doses of the Bristol-Myers Squibb (NYSE: [[ticker:BMY]]) anti-PD-1 antibody Opdivo (nivolumab) and stayed on therapy if they responded. If not, they