Expert Shares Efforts to Expand Use of CAR T-Cell Therapy to Solid Tumors

Natalie Sophia Grover, MD

CAR T-cell therapies have represented an exciting breakthrough in the treatment of patients with hematologic malignancies, according to Natalie Sophia Grover, MD; however, investigators are just scratching the surface of the potential of this modality, and work is needed to expand this approach to other diseases and solid tumors.

“We definitely need different and unique approaches with CAR T cells for solid tumors. It's probably going to be a slower process than it has been for hematologic malignancies,” said Grover. “It's going to take more innovation and more preclinical work. We need to examine different ways to improve trafficking to the tumor site and ways to counteract the immunosuppressive microenvironment.”

In an interview with OncLive, Grover, an assistant professor of medicine at the University of North Carolina Health, discussed ongoing research with CAR T-cell therapy in hematologic malignancies, efforts examining the potential for this approach in solid tumors, and future directions and challenges with this modality.

OncLive: Could you provide an overview of the current state of CAR T-cell therapy in hematologic malignancies?

Grover: In terms of hematologic malignancies, CAR T cells are [primarily utilized in] classic B-cell malignancies that express CD19. Particularly, there are FDA-approved products available for pediatric and young adult patients with relapsed/refractory acute lymphocytic leukemia (ALL). FDA-approved products are also available for those with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Soon, we're going to have approved products in the relapsed mantle cell lymphoma space, and [these agents are also being explored in] indolent lymphomas. In addition, we will soon have several approved products for patients with relapsed/refractory multiple myeloma in the form of BCMA CAR T-cell therapies. 

For [B-cell malignancies and multiple myeloma], we're most interested in figuring out where to place CAR T cells right now. Currently, products are approved for use in patients with relapsed/refractory disease, but the question, particularly in the lymphoma space, is: “Can we use these agents earlier on [in the treatment] process?” To this end, the ZUMA-7 trial is comparing the use of the CAR T-cell therapy axicabtagene ciloleucel (Yescarta; axi-cel) versus standard of care in patients with DLBCL who are in first relapse.

Additionally, with regard to B-cell lymphomas and leukemias, we are examining why some patients respond [to CAR T-cell therapy], while others do not. We are taking a closer look at mechanisms of resistance. Is it antigen escape or are there other reasons why patients are relapsing? We have really good products for patients with B-cell malignancies, but there's also interest in exploring other targets and other diseases.

Could you discuss the rationale for looking at CAR T-cell therapy in solid tumors? What are some of the challenges with implementing this approach?

We've seen great success in hematologic malignancies and there's interest in translating that into solid tumors. That being said, several challenges are faced in terms of solid tumors, one of the biggest being choosing a suitable antigen. For hematologic malignancies, specifically B-cell lymphomas and leukemias, CD19 is a great target. You're not as concerned about off-target toxicity; B-cell aplasia is something that we can live with.

For solid tumors, there's not a universally expressed target for a particular tumor type; it's hard to find a good target from that standpoint. The second problem is that many of these targets that we're looking at are expressed in normal tissue. [As such, you’re faced with the challenge of] on-target off-tumor toxicity, so there's concern about that, as well. In addition, for solid tumors, there's concerns about trafficking to the tumor site, [which makes it] a lot harder for the CAR T cells to get to the area of interest. Additionally, there’s a much more immune suppressive microenvironment, [ which again, makes it] harder for CAR T cells to get [where they need to go].

What is the safety profile of CAR T-cell therapy in hematologic malignancies? Could you expand on the potential events that present in solid tumors?

For hematologic malignancies, the unique toxicities that we've seen for CAR T cells are cytokine release syndrome (CRS) and neurotoxicity or immune effector cell-associated neurotoxicity syndrome. CRS is an inflammatory response that occurs with CAR T cells during expansion; it can range from mild symptoms, such as fever, to more significant toxicity, such as hypoxia, hypertension, and organ failure. One of the unique aspects is that when CAR T cells were initially approved for use in B-cell ALL, tocilizumab (Actemra), which is an anti–IL-6 receptor antibody, was also approved at the same time for treatment of CRS. Our knowledge of CRS has definitely expanded [since then]. Initially, we were more worried about treating it because we thought that you needed a significant response as part of the efficacy response to CAR T cells. Now, we're more comfortable with treating CRS early, so we're likely to give tocilizumab earlier than we used to.

Neurotoxicity with CAR T cells is a little bit more of a unique toxicity that people were initially less comfortable with. Sometimes [neurotoxicity] can [present in the form of] mild encephalopathy, confusion, or handwriting changes; however, it can range to be more severe encephalopathy or unresponsiveness, and some patients can get seizures. Some patients have even died from cerebral edema, although this is rare. We generally treat that [toxicity] with steroids, and we have definitely become more adept at treating it [over the years]. Some of the CAR T-cell products have more significant toxicity than others.

Some of the more specific toxicities for products are the on-target, off-tumor toxicity. For anti-CD19 CAR T-cells, we see B-cell aplasia, and then, depending on the target that we choose, we may see specific toxicities based on that target; this is a concern that we have for solid tumors. For example, in the abstract that I presented at this year’s ASCO Virtual Scientific Program, the target is mesothelin and that can also be found on the pericardium. One of the patients had mild pericarditis, which could be a specific on-target, off-tumor toxicity related to that specific target.

Have there been any preclinical or clinical data examining CAR T cells in solid tumors?

Several small trials on CAR T cells [in] solid tumors [have been done], but [the research is] still [in its] early [stages]. Most of the data that have been published so far are small, preliminary results of clinical trials. No findings have shown sustained, long remissions. The abstract I'm talking about at ASCO is on a specific anti-[human] mesothelin[-targeted] CAR T cell. This is interesting because, as opposed to using traditional viral transduction, investigators used mRNA transfection to manufacture the CAR T cells. They're actually using CAR peripheral blood mononuclear cells (PBMCs), as opposed to CAR T cells. [What makes] the mRNA transfection more unique is that it tends to be degraded by the body more quickly; it tends to be less persistent. One of the reasons to use that is that the CAR T cells can be destroyed more quickly; they don't persist as long. You can look at toxicities more carefully and if there's on-target, off-tumor toxicity that you're worried about, it is not going to be as big of an issue because it's not going to last as long. Also, when you use non-viral transduction, you also can potentially give more frequent infusions.

It's still very early, but the other thing that was interesting for their product was that the anti-human mesothelin-targeted CAR mRNA was transfected with PBMCs. Because it's a nonviral electroporation process, the manufacturing is quicker; it takes less than 1 day for manufacturing to take place. CAR T cells generally take weeks to manufacture. The third thing that was unique is the intraperitoneal administration, which allows for direct trafficking of the CAR PBMCs. [However], investigators have only treated 12 patients to date and this was a pilot study looking for feasibility. Although significant toxicity was not observed, they didn’t see as much efficacy either, although the results are still quite early. For future [efforts, they could consider] conditioning chemotherapy, which would be helpful before you give CAR T cells. Investigators were primarily looking at safety in the trial. They also didn’t allow for multiple cycles of infusions, so the question is whether you can potentially do multiple infusions and achieve improved efficacy.

What's your hope for the future of CAR T-cell therapy in solid tumors?

There's interest in different approaches, such as an armored CAR T cells, to counteract the immune-suppressive microenvironment in these tumors. There's also interest in addressing the concern about on-target, off-tumor toxicities. Factors such as safety switches are another possibility for solid tumors as a way to potentially combat the concerns related to toxicity.

Is there anything else from this presentation that you would like to highlight?

The initial abstract that I talked about looks at hematologic malignancies and where we've come from [in terms of treatment. It] looks at the long-term follow-up of CAR T cells for patients with B-cell lymphomas and chronic lymphocytic leukemia (CLL). It's actually one of the first trials of CD19-targeted CAR T cells that's based on axi-cel. Because this is one of the first trials of this product, it allows us to have follow-up of CAR T cells for B-cell lymphoma and CLL.

This study shows that a portion of patients in complete remission (CR) are still in remission many years out, with the longest patient in remission for 9.5 years. Although, you still can't definitively say that this [approach] is curative, we have more data to potentially show that it's possible to have very durable responses. With longer follow-up, we will be more comfortable saying that, potentially, there's a proportion of patients where CAR T cells could be curative.

The other abstract I'm discussing is on the use of CAR T cells in T-cell malignancies. T-cell malignancies have many unique issues. One of the concerns [in this space has to do with] fratricide, or the CAR T cells targeting themselves. If you're targeting an antigen on T cells, this may also release antigens on the CAR T cells. You have to come up with innovative ways to avoid that. One such way is GC027, an off-the-shelf CAR T-cell product that targets CD7-positive T-cell malignancies; it uses gene editing to edit out the CD7 on the CAR T cells. That way, the CAR T cells don't express CD7, and therefore, won’t target themselves.

The other main point from that presentation is on the use of off-the-shelf or allogeneic CAR T cells. Some of the issues we've seen in hematologic malignancies, but also in solid tumors, are related to CAR T-cell manufacturing. Many patients have been heavily pretreated, so it's hard to manufacture CAR T cells from these patients. One of the other issues is the timing of manufacturing. Some patients have really aggressive diseases, so oftentimes we don't have time to wait while CAR T cells are being developed.

Another issue is cost, specifically the cost of manufacturing an individual product for a particular patient. Off-the-shelf CAR T cells or CAR T cells manufactured from healthy donors, offer some solutions to this in terms of not having to worry about patients who are heavily pretreated, not being able to manufacture from them, and not having to worry about waiting while CAR T cells are being manufactured. It also reduced costs because these are not individualized for a particular patient.