Expanding Blood Cancer Care With the Next Frontier of T-Cell Immunotherapy

Few areas of blood cancer treatment have evolved as rapidly as T-cell–based immunotherapy. Chimeric antigen receptor (CAR) T-cell therapies and bispecific T-cell engagers have moved beyond their initial later-line applications and into earlier treatment settings across leukemia, lymphoma, and myeloma. Now, the field is pushing toward the next generation of immune-based therapies: trispecific T-cell engagers and “off-the-shelf” and in vivo CAR T-cell approaches that could address treatment resistance and ultimately make cellular therapies more accessible across care settings.

In recognition of September as Blood Cancer Awareness Month, Krish Patel, MD, executive director of hematologic cancer research at Sarah Cannon Research Institute, sat down with Targeted Oncology^TMto discuss these advances in T-cell–based immunotherapy and their potential to improve access to care.

Targeted Oncology: What immunotherapy advances in the last few years do you think have been the most impactful or practice-changing?

Krish Patel, MD: I would say the 2 most impactful in blood cancers have been the development of T cell-based immunotherapy, specifically both CAR T cell therapies and bispecific T-cell engagers. We've seen these [treatments used] across a lot of different disease states—lymphoma, myeloma, acute lymphoblastic leukemia—which have really changed the way we approach these diseases. They were initially developed as later-line therapies, but we've seen them move up into earlier-line settings across all these disease states.

I would highlight that while CAR T cells are a platform [where we still have] some work to do to improve access and the ability of patients regardless of where they live and where they get their care to access. Bispecific T-cell engagers, I think, have been able to extend that reach of T-cell–based immunotherapies to a lot more community settings where patients are receiving care, and so that's been really impactful.

As bispecifics move into the community setting, we are now also starting to hear about trispecifics. What problem is the trispecific approach trying to solve?

To set the stage, bispecific T-cell engagers work by engaging a single tumor antigen on the cancer cell, and then an antigen on an immune cell, like a T cell, to try to bring that T cell to kill the cancer cell. One mechanism of resistance is that the cancer cells can either lose under selective pressure, or if they never had that tumor-specific antigen to begin with, then that may allow the cancer to escape control from these T-cell–engaging therapies, and that's something we've been able to demonstrate in lymphoma, myeloma, and leukemias; you can lose that tumor-specific antigen that the bispecific targets. The trispecific T-cell engagers aim to take it one step further, target[ing] not 1 but potentially 2 different tumor antigens, and biologically, that may be harder for the tumor to lose both antigens, and so whether they have one or the other or both, they would be potentially subject to the antitumor effect of these trispecifics.

Another interesting platform for trispecifics is to look at the other side. Maybe you have 1 tumor cell antigen, but you could engage 2 different types of immune cells. These are also starting to be looked at, where maybe more than just a T cell, you can engage another type of immune cell or potentially engage another immune cell antigen for some other function to improve the T-cell killing. So, this ability to engineer antibodies and have multiple different targets is, I think, really exciting. And so, our earliest experience with these trispecifics is really when we're targeting 2 tumor antigens and trying to prevent that escape of the tumor due to so-called antigen loss.

While CAR T has been transformative, it remains a complex, resource-intensive therapy. How could allogeneic or in vivo CAR T change the way cellular therapy is delivered?

We know that autologous CAR T-cell therapy has really been transformative. But there are some technical considerations that make those therapies perhaps, in some settings, challenging to deliver. One of them is that you require the ability to collect immune cells from a patient through a procedure called leukapheresis, which is not [feasible] in every care setting. The other consideration is, you have to then be able to process those cells, send them to the manufacturer, and then receive back a product that you have to store and often cryopreserve. Those [processes] introduce infrastructure needs to be able to access [the CAR T].

A platform being developed to try to circumvent some of those infrastructure needs is an off-the-shelf CAR T. There, you would be thinking about a CAR T that's manufactured from either a healthy donor cell, so we don't have to collect them from the patient—that means we don't need leukapheresis capabilities—or even if you have [leukapheresis capabilities], sometimes we're not able to collect those immune cells from patients, so that's another theoretical benefit of that platform. The downside of off-the-shelf CAR Ts or allogeneic CAR Ts is that you do need to engineer those CAR T cells differently so that those immune cells that do not come from the patient don't result in other [adverse] effects, like graft-vs-host disease. There are some trade-offs of that platform, and there's been work ongoing on allogeneic CAR Ts for some time. I think our ability to do multiple gene edits in, say, a donor T cell have improved over time, so there's still reasonable opportunity to develop those platforms.

I think the field has moved even further along to think about, do we really even need to collect cells from anybody, whether that's the patient themselves or a healthy donor? Can we manufacture CAR T cells inside a patient's body? And that really is the approach that in vivo CAR T takes: Can we give a medicine that is essentially able to result in CAR T manufacture inside the patient's body [and yield] a form of gene therapy, where we can deliver a vector—whether a viral-based or mRNA-based vector—and allow the body to generate CAR T cells in the patient's own body?

What's exciting about both of those platforms is one can recognize that there may be less or different infrastructure needs for those therapies. I think on the other side of the coin, they are still very nascent technologies, and so we still have a lot to learn about the safety profile, the ultimate effectiveness, and durability of those therapies. But one could certainly see that if we're starting to see results that look comparable to autologous CAR T cells in terms of safety, efficacy, and long-term outcomes, then those platforms could really change how we think about access to cellular therapies because they could be delivered in many different care settings without the complex infrastructure needs that autologous CAR T cells require today.

Looking ahead, what are you personally most excited about as the treatment landscape evolves in the next few years?

I think there's a lot of buzz around in vivo CAR T cells. We have more and more coming to early-phase clinical trials and in the clinic, and so I think that's certainly an area that I'm very excited to see—what does that platform offer our patients in terms of easier access to really transformative therapies, and are they going to be as good and as safe as the current generation of CAR T cells?

What's also exciting about [bispecifics and trispecifics] is they are inherently a little bit more combinable with other therapies, and so we're also seeing as our ability to generate novel therapies proliferates rapidly, that these are treatments that can be combined with complementary therapeutic modalities like small molecule inhibitors, antibody-drug conjugates, [and] tools that can be readily accessed in community oncology settings. So these combination trials, I think, are also very exciting for what they mean for patients and what they could lead to in terms of better outcomes, potentially with less than or at least different adverse effects from what our traditional therapies have had.