Innovative Targets Enable Immunotherapy for Sarcomas

Sarcomas, which start in the bones and soft tissues, are a diverse group of rare cancers, with more than 70 different subtypes. Standard of care includes surgery, radiation, and chemotherapy, although advanced and relapsed cases often have few options aside from palliative care. Sarcomas represent an area which, despite recent advances in other kinds of cancers, has not yet seen success with immunotherapy, though not for lack of trying. 

“We use, mostly, the same therapies that we were using 20 and 30 years ago. So, for most patients diagnosed with a soft tissue or bone sarcoma today, the main parts of their treatment are surgery, radiation, and chemotherapy using drugs like doxorubicin and ifosfamide,” J. Andrew Livingston, MD, an associate professor in the department of sarcoma medical oncology and the department of pediatrics patient care at the University of Texas MD Anderson Cancer Center, told CGTLive™ in an interview. “On the one hand, we know we can cure a high number of patients with these treatments and they are highly effective. But on the other hand, there's been really limited improvements for patients when the standard treatments aren't effective.”

J. Andrew Livingston, MD

A Lack of Traditional Targets

Sarcomas represent a challenge for immunotherapies to target, especially as some subtypes do not have a high mutation burden to target. Recent efforts with the subtypes of synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCLS), sarcomas that start around the joints and in fat cells, respectively, have developed new innovations to identifynew targets for this historically evasive type of cancer. 

“There's been a long-standing interest in developing immunotherapy for sarcoma. But it's particularly challenging... we've looked a lot beyond immune checkpoint inhibitors to look at cell-based therapies,” Livingston said.

A newer strategy being evaluated on multiple sides targets cancer testis antigens (CTAs), such as NY-ESO-1 or MAGE-A4, that are typically not expressed on other normal tissues but can be expressed in very high levels in sarcomas, particularly SS and MRCLS.

“Over the past 5 to 10 years, with this recognition that there's really high levels of these CTAs expressed in these sarcomas, there have been studies looking at vaccine-based strategies or other adoptive cell therapies, trying to see how we can best target this,” Livingston said. “One of the challenges is because this is an intracellular protein, it tends to be expressed through the TCR T-cell receptor. So, for these types of antigens, actually, we can't use chimeric antigen receptor (CAR) T-based approaches. To date, most of the studies looking at targeting NY-ESO-1 or other CTAs for SS or MRCLS have been T-cell–based strategies.”

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MAGE-A4

Closest to the clinic and pending FDA approval is the MAGE-A4–targeted autologous engineered T-cell receptor (TCR) SPEAR T-cell therapy afamitresgene autoleucel (afami-cel; Adaptimmune Therapeutics) for HLA*02-positive patients. Afami-cel is one of the first cell therapies to be evaluated in clinical trials for sarcomas and solid tumors in general. (FIGURE)

I think, all of a sudden, we're going to be looking at huge screening efforts, probably done through genomics companies, that will identify these 3% of solid tumors. That doesn't sound like a lot until you realize how many solid tumors there are a year. And then we're going to have to adapt our ability to give this therapy, but I think, just as with all of the lymphoma and leukemia CAR Ts, you end up finding that, where there's a will, there's a way, to adapt these programs.

—Brian Van Tine, MD, PhD

The trial in question is the phase 2 SPEARHEAD-1 study (NCT04044768), which most recently had updated positive survival data presented atthe American Society of Clinical Oncology (ASCO) 2023 Annual Meeting, held in Chicago, Illinois, in June, by investigator Brian Van Tine, MD, PhD, professor of medicine and pediatrics at Washington University in St. Louis.¹

“If we can identify the right patients and treat them early, then all of a sudden, we get this patient autotreating themselves, and, especially when it works, this can go on for years, as we've seen in the clinical trials. I think it's interesting that afami-cel is now being considered for FDA approval, which will open up doors, I think, for this technology across other tumors and across other sarcomas,” Van Tine told CGTLive in an interview.

Brian Van Tine, MD, PhD

As previously reported, the overall response rate was 39% and the median duration of response was around 12 months.¹ The new data demonstrated that responders had a 1-year survival rate of 90% and a 2-year survival rate of 70%. The median overall survival (OS) rate overall was 17 months although the median OS has not yet been reached for responders. Comparatively, second-line treatment of advanced synovial sarcoma has historically yielded a median OS of under 12 months. The new data also included transient cases of cytokine release syndrome but no new, long-term safety signals. Adaptimmune initiated the rolling biologics license application for afami-cel in the synovial sarcoma indication in December 2022.²

“(These programs) are still HLA-restricted, so you have to have the right kind of immune system with a classic HLA that was studied in the lab, which is why I think HLA*02 was chosen, which, unfortunately, is mostly restricted to people of Northwest European origin, who then express either MAGE-A4 or NY-ESO-01,” Van Tine noted. “There are hints that something else is coming. Same idea, same technology, but different markers, which may go across more sarcomas, which is exciting.”

NY-ESO-1

Another newer therapy making its way to clinical trials is the collaboration between Syena, a subsidiary of Replay, and MD Anderson to assess the NY-ESO-1 TCR/IL-15 NK TCR natural killer (NK) cell therapy for the same SS and MRCLS indications. The therapy was cleared to initiate clinical trials in the United States in June 2023 and the collaborators are speeding to officially open the trial, for which Livingston will serve as primary investigator of.³ The planned phase 1/1b clinical trial will evaluate the safety and efficacy of the therapy in approximately 44 patients with SS or MRCLS. Patients will undergo lymphodepletion via fludarabine/cyclophosphamide, which will be administered in standard doses, before being treated with NY-ESO-1 TCR/IL-15 NK.

While afami-cel is novel for targeting MAGE-A4, Syena’s therapy is not the first to target NY-ESO-1 for SS and MRCLS, although it may be the first to combine the strategy with NK cell therapy. In fact, Adaptimmune just recently reached an agreement with GlaxoSmithKline to get its NY-ESO-targeted TCR program, letetresgene autoleucel (lete-cel), back from the company as well as another TCR program targeting PRAME, which is another CTA.⁴

Patients with advanced /metastatic MRCLS have received lete-cel in a phase 2 trial (NCT02992743) which Van Tine was also involved with and has shown some promising data, including an ORR of 40% and a progression-free survival of 8.7 months in cohort 2, and a tolerable safety profile.⁵ Lete-cel also previously showed efficacy in a separate study in patients with SS (NCT01343043). Another NY-ESO-1-targeted TCR therapy, TAEST16001, is being evaluated in patients with soft tissue sarcomas in a phase 1 trial (NCT04318964) at Sun Yat-sen University in China, which presented similar data to lete-cel, also at the ASCO 2022 meeting.⁶

“There are so many unique subtypes [of sarcoma] with their own biology, their own molecular drivers, things that may yield responses to one type of therapy, but not another. We have to work to keep those straight and then to develop subtype specific therapies for sarcoma. This is a lot of where the field has gone in the last 10 years and is continuing to go—not thinking about all sarcomas together, but really diving into the unique molecular drivers to derive really subtype-specific therapies,” Livingston said, looking forward.

REFERENCES

1. Van Tine BA, Ganjoo KN, Blay JY, et al. The SPEARHEAD-1 trial of afamitresgene autoleucel (afami-cel [formerly ADP-A2M4]): Analysis of overall survival in advanced synovial sarcoma. Presented at: ASCO 2023 Annual Meeting; June 2-6; Chicago, Illinois. Poster #497
2. Adaptimmune announces initiation of Biologics License Application (BLA) Submission for Afami-cel, Itsfirst-gen engineered TCR T-cell therapy targeting MAGE-A4, for the treatment of synovial sarcoma. News release. Adaptimmune. December 23, 2022. Accessed August 10, 2023. https://www.adaptimmune.com/investors-and-media/news-center/press-releases/detail/237/adaptimmune-announces-initiation-of-biologics-license
3. MD Anderson and Replay announce FDA clearance of IND application for first-in-class TCR NK cell therapy for sarcoma. News release. MD Anderson. June 20, 2023. Accessed August 101, 2023. https://www.mdanderson.org/newsroom/novel-tcr-nk-cell-therapy-sarcoma-receives-ind-clearance-fda.h00-159619434.html
4. Adaptimmune and GSK Have Agreed Terms for Transfer of PRAME and NY-ESO Target Programs back to Adaptimmune. News release. Adaptimmune. April 11, 2023. Accessed August 11, 2023. https://www.adaptimmune.com/investors-and-media/news-center/press-releases/detail/243/adaptimmune-and-gsk-have-agreed-terms-for-transfer-of-prame
5. Primary efficacy and safety of letetresgene autoleucel (lete-cel; GSK3377794) pilot study in patients with advanced and metastatic myxoid/round cell liposarcoma (MRCLS). Presented at: ASCO 2022 Annual Meeting; June 3-7; Chicago, Illinois.
6. Zhang X, Weng D, Pan Q, et al. Phase I clinical trial to assess safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of NY-ESO-1–specific TCR T-cells (TAEST16001) in HLA-A*02:01 patients with advanced soft tissue sarcoma. Presented at: 2022 ASCO Annual Meeting, June 3-7, 2022. Abstract #11502