Burgeoning Immunotherapy Options in Oncology Move Beyond CAR T and the Usual Disease States

The use of immune therapies for hematological malignancies is expanding beyond chimeric antigen receptor (CAR) T-cell therapies in the traditional lymphoid disease states, but the impact on patient quality of life must remain top of mind.

Professor Hermann Einsele, of Universität Würzburg in Germany, chaired the session at the European Hematology Association 2023 Congress, and he kicked it off by noting that despite the intense attention on CAR T-cell therapies in recent years, they are not the only immunological therapy available, and there have been many developments in other areas.

One such development is the use of T-cell receptor (TCR)–engineered T cells, in which the cells are manipulated ex vivo to express certain TCRs, explained the first presenter, Professor Emma Morris, of University College London. T-cell signaling is complex, she said, and the arrangement of receptors is important in the downstream signaling pathway.

TCRs are human leukocyte antigen (HLA) restricted, so “that makes the translation of these therapies difficult, because the recipient has to express the same HLA molecules,” Morris said. However, the advantages of TCRs include that they are able to recognize neoantigens in the cancer mutagenome, making them better at discriminating these tumor cells.

Alongside the refinement of CAR T-cell therapies into the next generation that can recognize abundant cell surface antigens, the same approaches are being used to improve next-generation TCR T cells by optimizing TCR pairing and preventing mispairing, which can be achieved through the use of CRISPR or other gene editing approaches.

Morris highlighted several examples of ongoing research in the TCR space, such as the investigation of whether adding more CD3 to the TCR complex could enhance the therapeutic effect without increasing mispairing. Investigators are also looking into whether TCR-based therapy could target solid tumors more effectively than CAR T.

For instance, Ruggieri et al demonstrated in a 2022 study the promise of a genome editing approach that could avoid mispairing and maximize TCR expression and function, which showed efficacy in killing acute myeloid leukemia (AML) blasts, acute lymphoblastic leukemia blasts, and glioblastoma cells in vitro and in vivo.¹ Also published last year was a study by Omer et al that used a costimulatory CAR to boost the activity of T cells expressing TCRs, which enhanced antitumor response.²

While TCRs are not yet ready to challenge CAR T for dominance in the immunotherapy space, Morris said, investigators are “trying to target difficult solid tumors in a hostile microenvironment where we have to use all of these novel engineering techniques, because, remember, the [TCR] is fantastic; it’s why our T cells work…. They are exquisitely sensitive, exquisitely discriminating, and able to recognize very, very low levels of target antigen.”

The next speaker, Professor Stephan Mielke, of Karolinska Institutet in Stockholm, Sweden, began his presentation by recalling that at an EHA congress 6 years ago, he delivered a talk on how to build a CAR T-cell therapy center; today, such a talk would draw no audience because the number of centers has already exploded.

Mielke explains CAR T-cell engineering to patients as giving their cells glasses to make them see something they otherwise wouldn’t, as they usually look intracellularly. This approach has demonstrated incredible results, largely in lymphoid malignancies and with mechanisms that target CD19 or B-cell maturation antigen, but there are still unmet needs.

“When we get a new tool like CAR T cells or targeted therapy or checkpoint inhibitors, we always have the mindset, ‘Now we’re going to cure cancer, we’re going to use it for all the diseases,’ but then we are learning that it will not work for all diseases,” Mielke said. For instance, AML is difficult to treat because the tumor lacks perfect antigens, but IL-1RAP could be an ideal target for CAR T cells in this disease state because its expression is restricted to malignant cells and monocytes.

Even more difficult to treat with CAR T cells are solid tumors, he continued, due to several factors including T-cell dysfunction within the tumor microenvironment and that one side of a tumor might have completely different antigen expression than the other side of the tumor.

Some ongoing subjects of investigation that Mielke highlighted included BNT211-01, which showed an ongoing effect of CAR T cells in testicular cancer; NY-ESO-1 as a target in patients with sarcoma; and CD70, which he called “a promising pan-cancer antigen” that can be found in the vast majority of tumors. Future directions for research on CAR Ts could include CRISPR engineering and use in combination with checkpoint inhibitors or radiotherapy.

He concluded by thanking the patients who put their trust in the clinicians and researchers working on CAR T therapies, which obligates them to share these findings at conferences for the benefit of their patients.

The session ended with the perspective of a patient advocate, Hans Scheurer, who has had myeloma since 2005 and is currently chair of the Workgroup of European Cancer Patient Advocacy Networks.

He emphasized that quality of life is the key end point for patients with cancer. Measuring value by patient experience can be difficult and often labeled as subjective, he said, but that’s not an excuse for regulators to refuse to collect and use these data.

“Avoiding it is not helping you get a better insight on its value of making real differences,” Scheurer said.

For instance, clinicians may assume that patients will universally want a therapy that can extend their life, but in actuality some patients will not want to undergo severe adverse effects for just a few more months of survival.

Myeloma Patients Europe, which Scheurer served as president of from 2016 to 2022, interviewed 11 patients receiving CAR T-cell therapies, who praised the good quality of life yielded by the treatment—one patient was quoted as saying, “For the first time, I felt as good as before my diagnosis.”

Some drawbacks reported by the patients included travel time to the CAR T center, fear of disease progression while the cells are being modified in the laboratory, and the immune vulnerability that comes with the treatment approach, which is of particular concern as society is largely moving past the COVID-19 pandemic precautions.

The takeaways from patients are that while they’re excited by the impressive results of immunological approaches to cancer, they want more research on the variation in adverse effects during treatment and beyond, as many are concerned about long-term brain effects and immune effector cell-associated neurotoxicity syndrome.

From the clinician perspective, Morris asked Scheurer what types of factors go into patients’ decisions to take part in a phase 1 trial. Most commonly, patients joining these early-stage trials have run out of other treatment options, he said, but transparency is key to making an informed decision.

“Have that conversation and be honest about what you offer, not only data on a few extra months [of survival], but what is the impact on your life of having these side effects,” he recommended.

References

1. Ruggiero E, Carnevale E, Prodeus A, et al. CRISPR-based gene disruption and integration of high-avidity, WT1-specific T cell receptors improve antitumor T cell function. Sci Transl Med. 2022;14(631):eabg8027. doi:10.1126/scitranslmed.abg8027

2. Omer B, Cardenas MG, Pfeiffer T, et al. A costimulatory CAR improves TCR-based cancer immunotherapy. Cancer Immunol Res. 2022;10(4):512-524. doi:10.1158/2326-6066.CIR-21-0307