Here to Stay: Progress Solidifies the Future of Cell Therapy

In recent years, the use of cell therapies to treat hematologic malignancies has moved into the mainstream, with therapies such as Breyanzi (lisocabtagene maraleucel), Tecartus (brexucabtagene autoleucel), Yescarta (axicabtagene ciloleucel), and Kymriah (tisagenlecleucel) earning approval for treating myelomas, leukemias, and lymphomas. For solid tumors, though, obstacles to bringing effective cell therapies to clinic have left these patient populations waiting. Traditional cell therapy approaches, such as chimeric antigen receptor (CAR) T-cell therapies, have so far been unsuccessful in treating solid tumors because of unique challenges in these types of cancers, including tumor heterogeneity, targeting difficulties, and the tumor microenvironment.

Although, treatment development tactics have begun to meet these challenges head on, and with creativity. Newer-generation cell therapies combine strategies to help combat these challenges, using T-cell receptors, tumor-infiltrating lymphocytes, oncolytic viruses, antigen presenting cells, and other strategies to enhance the harnessing of the body’s natural immune response (FIGURE).

"For a long time, we thought that cell therapy was just going to be a hematologic malignancy thing. With the scientific advances in the last couple of years, I think it's very clear that solid tumor cell therapy is here. It's here to stay. It's going to get approved soon. And when we think about the numbers of patients with solid tumor versus hematologic malignancies, realistically, we're going to start treating a lot more patients with solid tumors,” Alison Betof Warner, MD, PhD, a medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center, told CGTLive^™.

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Afamitresgene Autoleucel

One such therapy that has shown unprecedented efficacy in recurrent/refractory synovial sarcoma (SS), an indication that historically hasnot seen much long-lasting results, is afamitresgene autoleucel (afami-cel; Adaptimmune Therapeutics). Afami-cel is an investigational autologous engineered T-cell receptor (TCR) SPEAR T-cell therapy intended to target MAGE-A4-expressing solid tumors that is being evaluated in the phase 2 SPEARHEAD-1 study (NCT04044768), which last reported positive data in November 2022.¹

“What is interesting about SS is that if you can find a patient that's HLA-A*02, they have about 60% to 80% chance of expressing the target. This happens across all solid tumors, but not at this rate. It may be 1%, it may be 2%, but we need to identify these patients. There are a lot of screening efforts going on, because not only is this a wonderful therapy with durability, [but] some patients are now doing well after a single treatment at 3 years. Afami-cel is going to go across solid tumors once we can find and identify those patients,” SPEARHEAD-1 study investigator Brian Van Tine, MD, PhD, a professor medicine and pediatrics at Washington University in St. Louis, told CGTLive.

The most recent data were from 52 participants enrolled in cohort 1 of the trial with MAGE-A4-positive recurrent/refractory cancers, including SS (n = 44; 84.6%) and myxoid/round cell liposarcoma (MRCLS; n = 8; 15.4%).¹ There were no complete responses (CR), but were 19 partial responses (36.5%), 27 cases of stable disease (51.9%), and 6 cases of progressive disease (11.5%), for a total overall response rate (ORR) of 36.5% (95% CI, 23.62-51.04). By disease, the ORR in SS was 38.6% (95% CI, 24.36-54.50) and the ORR in MRCLS was 25.0% (95% CI, 3.19-65.09). Eight responses were ongoing as of the data cutoff date.

Most participants (n = 27; 71.2%) experienced cytokine release syndrome, although all cases but 1 were below grade 3. Cytopenia was common and 1 participant experienced immune effector cell-associated neurotoxicity syndrome below grade 3. Van Tine discussed the data and the potential of cell therapy to change outcomes in refractory/recurrent SS with CGTLive while on-site at the the 2023 Tandem Meetings |Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, held in Orlando, Florida, February 15-19.

Hear more in detail from Van Tine in the video below.

"When we put up the first data set, where some patients were doing well a year after treatment with a durable response, it was early days, it was a phase 1 trial, and it changed a lot of my European colleagues' opinions. I remember being in the Speaker's room at ESMO, getting a very hard time about presenting this data. And they all completely changed sides after they saw the slider plot, because this is an easy one, when you look at it, it just works when it works."

— Brian Van Tine, MD, PhD

Importantly, investigators also found that afami-cel facilitated the movement of cytotoxic T-cells into tumors, and responders had tumor microenvironments shift from being immunosuppressive to proimmune. The therapy was also evaluated in a phase 1 clinical trial (NCT03132922) which reported data in January 2023 that showed that among 16 treated patients with SS, the ORR was 44% (n = 7) and the median duration of response (DOR) was 28.1 weeks (95% CI, 2.286-not reached [NR]).² However, for the 22 treated patients with other tumor types, the ORR was much lower at 9% (n = 2). It was noted that all responses seen in the trial across all tumor types were partial responses, and the median DOR for all treated patients was 25.6 weeks (95% CI, 12.286-NR).

“There's some really impressive data in several types of sarcomas and a registrational trial going on right now with potential approval in the next couple of years. I think that's a disease that we never thought would be immune-responsive, and so that’s really exciting and there’s more data to come... Sarcoma trials are so hard to do, because it's such a rare disease. And so just the fact that they've been able to even get this done is just a huge accomplishment,” Betof Warner said, referring to the SPEARHEAD-1 trial.

Gemogenovatucel-T

Other promising cell therapy ventures into sarcoma include Gradalis’ autologous tumor cell therapy gemogenovatucel-T (Vigil) that expresses bi-shRNA furin/GMCSF plasmid and is being evaluated for both Ewing sarcoma (NCT02511132) and ovarian cancer (NCT02346747). Data from March 2023 showed that a combination of Vigil, temozolomide, and irinotecan yielded 2 partial responses as measured by response evaluation criteria in solid tumors (RECIST), which became histologic CRs without additional therapy at long-term follow-up out of 6 evaluable participants.² Overall, 5 participants experienced at least stable disease for at least 6 months and the mean progression-free survival was 8.2 months (95% CI, 4.3-NA), while 1-year overall survival (OS) rate was 62.5% (95% CI, 36.5-100), and median OS was 18.5 months (95% CI, 8.2–NA).

“One of the important things that we've been trying to stress is the integration of solid tumor doctors into care, and not just sort of plugging solid tumor patients into the traditional heme cell therapy model, because there's different problems with different complications. These patients are coming. And we all need to be ready for it.”

–Alison Betof Warner, MD, PhD

Alison Betof Warner, MD, PhD

Lifileucel

Although Warner was enthusiastic about the data observed in sarcoma, she was most excited for the tumor-infiltrating lymphocyte (TIL) therapy lifileucel, a pioneering cell therapy for solid tumorswhich has a biologics license application (BLA) that the FDA is currently reviewing after Iovance Biotherapeutics completed its submission at the end of March 2023.³

“In melanoma, we expect that TIL will be approved, probably in 2023. Traditionally, what we've seen is that patients may have a great response to checkpoint blockade, but if they are a nonresponder to checkpoint blockade for melanoma, there are very few treatment options for them, and the median overall survival is usually measured in short months for those patients,” Warner said. “Over the last year or 2, we've seen really impressive data for TIL, suggesting that there's about a 31% response rate. But the patients who do respond tend to have very durable responses, with about 40% of them still responding 2 years later to a 1-time treatment. And so, for patients with melanoma that have progressed on checkpoint blockade, this is really the only option for a durable treatment strategy. That's what we're really excited about. We've seen quite a bit of evolution in TIL over the last year, but a lot of data have emerged for lifileucel in particular.”

Lifileucel’s BLA is for unresectable or metastatic melanoma that progressed on or after prior anti-PD-1/L1 therapy, and if BRAF mutation positive, also prior BRAF or BRAF/MEK inhibitor therapy. The therapy most recently demonstrated positive data from the phase 2 C-144-01 clinical trial (NCT02360579) in late 2022, with an ORR of 31.4%, a median DOR not reached at a median follow up of 36.5 months, and 41.7% of responding patients reaching a DOR of 24 months or more.⁴ Median OS was 13.9 months, and the 12-month OS rate was 54% (95% CI, 45.6-61.6). The safety profile was manageable, with most TEAEs transient and consistent with lymphodepletion and IL-2.

Lifileucel is also being assessed in combination with pembrolizumab in the recently announced, phase 3 confirmatory TILVANCE-301 study which is primarily assessing ORR and progression-free survival. The study will support full approval of lifileucel in post-anti-PD-1 advanced melanoma and will support another indication for frontline treatment of advanced melanoma.

Progressing Preclinically

“If we think about where we came from 3 years ago, where you could count on both hands the number of cell therapy trials there were actively enrolling patients for solid tumors, the growth of this field is just so fun to be a part of," Warner added. "One thing that we're seeing is, especially with solid tumors, really moving away from CAR, or at least traditional CAR, and moving more towards TIL in melanoma and many other solid tumors, TCR products, bispecific engagers, and other modes. But I think we will also start to see some hybrid of those technologies, like modifying TIL by putting TCRs on TIL, for example. To me, that's where the future of this field lies. I think we're really right now just at the very tip of the iceberg, and there's a lot to come. I think what we'll start to see is integration of a lot of the technology that we've seen in CAR come to TCR-based products, TILs, and other things."

Marco Davila, MD, PhD

Supporting the emergence of cell therapy in treating solid tumors is preclinical research, such as that conducted in the lab of Marco Davila, MD, PhD. Davila is senior vice president and associate director of translational research, and vice-chair of cellular therapies at Roswell Comprehensive Cancer Center. His research aims to answer the lingering questions about cell therapies’ lack of efficacy in solid tumors until recently and strategies to improve said efficacy. Davila’s research has recently identified pro- and antitumor phenotypes of myeloid cells that may correlate with responses to cell therapy, and how these phenotypes could possibly bechanged.^5,6 Davila shared a similar outlook to that of Van Tine and Warner about the future of cell therapy in solid tumors.

“I'm directing a lot of my research now towards the solid tumor field, which we think is the next big hurdle or opportunity for gene-engineered cell therapies. I'm really excited for the next 5 to 10 years for research—not just from my lab, but from labs all over the world. Hopefully, we're going to start delivering some good outcomes for patients with solid tumor malignancies,” Davila told CGTLive.

REFERENCES
1. Van Tine BA, Araujo DM, Blay JY, et al. Final analysis from SPEARHEAD-1 cohort 1 of afamitresgene autoleucel (“Afami-cel” [formerly ADP-A2M4]) in advanced synovial sarcoma and myxoid/round cell liposarcoma. Presented at: 2022 CTOS Annual Meeting, November 16-19, 2022, in Vancouver, BC.
2. Hong DS, Van Tine BA, Biswas S, et al. Autologous T cell therapy for MAGE-A4+ solid cancers in HLA-A*02+ patients: a phase 1 trial. Nat Med. 2023:29:104-114. doi:10.1038/s41591-022-02128-z
3. Anderson P, Ghisoli M, Crompton DB, et al. Pilot study of recurrent Ewing's sarcoma management with vigil/temozolomide/irinotecan and assessment of circulating tumor (ct) DNA. Clin Cancer Res. Published online March 16, 2023. doi: 10.1158/1078-0432.CCR-22-2292
4. Iovance Biotherapeutics completes Biologics License Application (BLA) submission for Lifileucel in advanced melanoma. News release. Iovance Biotherapeutics. March 24, 2023. Accessed April10,2023.
https://finance.yahoo.com/news/iovance-biotherapeutics-completes-biologics-license-200100220.html
5. Sarnaik A. Lifileucel TIL cell monotherapy in patients with advanced melanoma after progression on immune checkpoint inhibitors (ICI) and targeted therapy: Pooled analysis of consecutive cohorts (C-144-01 study). Presented at: Society for Immunotherapy of Cancer’s (SITC) 37th Annual Meeting November 8-12, 2022; Boston, MA. Abstract #789
6. Davila ML. Mechanisms of Resistance to CD19-Targeted CAR T Cells: Lessons from Mice and Patients. Presented at: Tandem Meetings; February 15-19, 2023; Orlando, Florida.