Advancing Cellular Therapies in Solid Tumors: Current Challenges and Future Directions

Jay Spiegel, MD

Investigators have not been able to replicate the success seen with cellular therapy in hematologic malignancies. However, clinicians are hopeful that this therapy could prove to be a meaningful treatment option for patients in need with refractory solid tumors, according to Jay Spiegel, MD.

“CAR T and cellular therapy has made extraordinary advances in hematologic malignancies in the past five years. We’ve been able to, I hope we can say, cure patients who would otherwise have not been able to be cured with these therapies. Solid tumors represent in some ways the next frontier. Although the days are still early, some of the advances that we’ve seen with tumor-infiltrating lymphocytes [TILs] in melanoma suggest that we may eventually be able to cross that frontier and bring these therapies to patients who are in need in the solid tumor space,” Spiegel explained.

In an interview with OncLive^®, Spiegel, an assistant professor at Miami Miller School of Medicine and a transplant and cellular therapy physician at Sylvester Comprehensive Cancer Center in Florida, discussed the status of CAR T-cell therapy in solid tumors, highlighting challenges such as tumor microenvironment complexities and target antigen limitations.

OncLive: What jumpstarted interest in CAR T-cell therapy for solid tumors?

Spiegel: CAR T-cell therapy is approved for the treatment of [patients with] lymphoma, leukemia, and myeloma. These agents have proven surprisingly effective for patients with refractory cancer and have had multiple approvals since 2017. But there’s huge unmet need in patients with refractory solid tumors. There’s been a lot of recent interest in trying to bring these types of therapies into the solid tumor space to see if they can [lead to more] cures or [simply] responses in patients who have highly refractory solid tumors.

What have been some of the challenges with cellular therapy treatment in solid tumors?

The stance of CAR T-cell therapy in solid tumors [is] that it’s been difficult. Everything remains in relatively early-phase [study]. CAR T involves taking somebody’s own T cells and genetically reengineering them to find cancer. An approach that is much older for the treatment of solid tumors is to [use] TILs that are immune cells that are already present in the cancer. [TILs are] able to get [into the tumor], which is a big problem with CAR T. [TILs are] already resident in the tumor, they may already recognize neoantigens or unique presentations of the tumor that might not be easily targetable with CAR T. And those [cells] are taken out, processed, grown, and turned into a cell therapy product, [which is] then given back to the patients.

Recently the FDA approved the first ever cell therapy for solid tumors, the TIL therapy lifileucel [Amtagvi] in melanoma. That’s really the approach that’s had the most success. CAR T has some limitations in that it can only target an extracellular protein, whereas TILs can target intracellular antigens, which give it a wider scope.

But CAR T also has to be able to get into the tumor, they have to deal with the tumor microenvironment, which is also true for TIL, but it can be particularly challenging in the setting of CAR T-cell therapy. And CAR T tends to only be able to target one antigen or even two antigens at a time. Solid tumors are more complex than hematologic cancers, so it may be hard to find an antigen that’s expressed on every cancer cell. Additionally, a lot of these targets are also present on normal tissues. So, for example, in hematologic malignancies, the main target in lymphoma is CD19, which is present primarily on B cells. You can lose your normal B cells and still survive [because] you can get replacements with IVIG. But for example, with mesothelin-targeting CAR T-cell therapy, mesothelinis present in the lung, and attacking the lung tissue can cause pneumonitis and [other] significant on-target but off-tumor toxicities. Those are some of the major issues confronting CAR T in the solid tumor setting.

Are there any current trials that you are keeping your eye on in this space?

The most advanced data that we’re awaiting is with the TIL therapy C-145 in cervical cancer, [which is developed by] the same company that produces lifileucel. We have the trial open at the University of Miami. [The investigators] last presented data in 2019, which everybody was excited about. But with changes to the cervical cancer landscape, namely the use of checkpoint inhibitors earlier on in lines of therapy, the FDA asked the trial to enroll more patients who had been treated previously with checkpoint inhibitors. That’s the most advanced therapy in gynecologic oncology that might lead to an approval.

There have been various other approaches using TCR-targeting MAGE, for example. But that trial was taken forward only for synovial sarcoma. It was studied in ovarian cancer, but we didn’t see the responses we would like. Similarly, there was a localized effort from Memorial Sloan Kettering Cancer Center with the MUC-16(ecto) CAR. They last presented [data with that agent] in 2020. They’ve been working on that, but I don’t think that’s necessarily close to the clinic in any appreciable way. We [have to go] back to the drawing board as far as using cell therapy in gynecologic malignancies outside of the TIL therapy I mentioned.

How will the approval of lifileucel inform the use of cellular therapy in other solid tumors?

That study, which was published in the Journal of Clinical Oncology in 2021, enrolled patients with metastatic melanoma post PD-1 and BRAF inhibition plus or minus a MEK inhibitor. Of the 66 treated patients the overall response rate was 36% with a median overall survival of about 18 months. We received the approval [about a month ago] and patients are already starting to undergo procedures for TIL harvesting. I don’t believe anybody has been treated commercially yet because it takes approximately 3 weeks to make the product. As far as what it holds for solid tumors, it will be important to see how the product is going to perform outside the clinical trial setting. We always have to think about the generalizability of trial results because patients outside of the clinical trial setting may not match [the description of those who participated in the trial].

The success of manufacturing the TIL product, which entails undergoing surgery and having the company successfully make the product, will be important to see. With some CAR products that manufacturing process has been more difficult than [with] other [therapies]. Regarding whether [the therapy is] directly applicable [to other solid tumors], melanoma is a disease that is famous for having great responses to immune-based therapies, which have not necessarily translated to every solid tumor. It’s hard to draw direct comparisons there, but as far as the functionality of a TIL product in practice in the general community, [lifileucel will] be something we can learn from.

What other types of cellular immunotherapy could emerge as a potential treatment modality in solid tumors?

The vaccine approach, which is kind of an old approach made new again, with some of the mRNA vaccine approaches is an exciting area to keep track of. I haven’t been part of any of those trials, but that might be another avenue of utilizing the immune system that we haven’t necessarily seen commercial success with. Ultimately, the thing about CAR T that may hopefully allow it a future in solid tumors is that it can be iteratively updated, because you’re already utilizing genetic modifications. In theory, that’s limitless, though it likely isn’t because of changes you can cause to the genome and secondary problems.

We’re in the early phases of learning how to make cell therapies work. CAR is an adaptable cell therapy in that we can continue to work on what makes the best receptor and what makes the best combination of targets, looking at gating strategies where you need to trigger on two targets, not just one to hopefully avoid on-target, off-tumor toxicities. The future is bright in that sense, but we still need that next jump in technology to be able to achieve success. Where we are now, I’m a little less bullish on. There needs to be some advances that will come into the scientific community before it can become a reality.

What does the future hold for these therapies?

My old boss from fellowship used to say that this version of CAR T-cell therapy is like the Nokia phone from the 1990s. Looking at a lot of scientific advances that our colleagues are making in the field as far as how to learn more about why particular CAR T cells work, what makes the best T cells to turn into a CAR, those are the things that I have the most excitement about in terms of seeing how we evolve as a field, because we do need to evolve. We’ve had exciting successes, but these are still barriers we need to overcome. In the near future, it’s going to be [about] phase 1 clinical trials, and hopefully, we’re going to learn more, but I’m excited to see what we can come up with from the scientific perspective.

Reference

1. Peterson C, Denlinger N, Yang Y. Recent advances and challenges in cancer immunotherapy. Cancers (Basel). 2022;14(16):3972. doi:10.3390/cancers14163972