Cellular Therapies Move Forward in Lymphomas and Leukemias, But Challenges Remain

Abhinav Deol, MD

Great strides have been made with CAR T-cell therapy in different lymphomas and leukemias, which have allowed many patients to achieve durable responses, according to Abhinav Deol, MD, who added that identifying mechanisms of resistance and examining checkpoint inhibitors following relapse on this modality are now active areas of exploration.

“CAR T-cell therapy is an important modality of treatment; although, prior to therapy, patients must have good performance status and social support. As such, CAR T-cell therapy may not be the best option for every patient,” Deol explained. “Follow-up is needed because some patients may experience delayed neurological toxicity. Some may have long-term adverse effects, such as hypogammaglobulinemia, which could require ongoing immunoglobulin replacement, or cytopenias that can last for 6 months to 1 year after the infusion. We continue to gain experience with this therapy, and we expect to see additional approvals in the near future, which will move the field of cellular therapy forward.”

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on Leukemia and Lymphoma, Abhinav Deol, MD, associate clinical professor, Barbara Ann Karmanos Cancer Institute, highlighted the progress that has been made with CAR T-cell therapy in leukemia and lymphoma, challenges faced with regard to accessibility and toxicity, and next steps for this modality.

OncLive^®: What are some of the key advances that have been made with CAR T-cell therapy in leukemia and lymphoma in recent years?

Deol: We have seen a lot of clinical data regarding the approved CAR T-cell products: tisagenlecleucel (tisa-cel; Kymriah), brexucabtagene autoleucel (Tecartus) and axicabtagene ciloleucel (axi-cel; Yescarta).

In terms of tisagenlecleucel, we [have seen] long-term response rates in certain patients with acute lymphoblastic leukemia (ALL), with a median progression-free survival (PFS) of about 19 months. We saw longer follow-up data with the ZUMA-1 study as well as the tisagenlecleucel registration study, which showed complete response (CR) rates of around 40%. Patients were relatively stable beyond 1 year of therapy, with hardly any relapses.

New and exciting data [have also emerged] with brexucabtagene autoleucel; we saw a nearly 90% response rate with about a 62% CR rate in patients who were very heavily pretreated for mantle cell lymphoma (MCL).

Additionally, findings from a study that is [examining lisocabtagene maraleucel (liso-cel)in] patients with diffuse large B-cell lymphoma (DLBCL) have also read out. Again, the response rates are similar, around 70%, with long-term CR rates of around 50%.

Some ongoing clinical trials [are examining this modality] in other indications, like chronic lymphocytic leukemia (CLL). In this disease, [we have seen that] that patients who are refractory to venetoclax (Venclexta) and ibrutinib (Imbruvica) respond well to anti-CD19 CAR T-cell therapy and have responses that have persisted for over 1 year.

ZUMA-7 is another anti-CD19 CAR T-cell study that is being done in [patients with] indolent non-Hodgkin lymphoma. The ZUMA-7 study treated about 140 to 150 patients, a majority of which responded to [axi-cel]. Even with a short follow-up, those responses proved to have some durability. We have to keep in mind that [in this disease], shorter follow-up may not reveal late relapses; we need longer-term follow-up to tell us more about that.

Could you expand on some of the data reported with tisa-cel in ALL?

The original study included pediatric patients while subsequent studies included young adults up to the age of 25. Currently, the approval is for patients with ALL who are 25 years or younger and who have relapsed/refractory disease; it’s not approved for older patients at this time. Patients were found to have good response rates with the product and the responses appear to be stable.

The rates of cytokine release syndrome and neurotoxicity are higher compared with [what was seen in] the lymphoma population, which could correlate to the disease burden going into the CAR T-cell therapy. Investigators are now looking at using cytoreduction to achieve the optimal amount of disease prior to undergoing CAR T-cell therapy to help improve outcomes.

In recent years, it has become more evident that CAR T cells might be curative in pediatric populations. Conversely, in older patients, there is a suggestion that even patients who achieve CR might need a subsequent allogenic stem cell transplant to help them stay in remission. Investigators in China, as well as researchers at Fred Hutch, have demonstrated this.

How does brexucabtagene autoleucel differ from the other approved agents that are available?

In recent years, several newer agents have been developed in MCL, such as the BTK inhibitors [and now, CAR T-cell therapy]. The patient population enrolled to the registration study of brexucabtagene autoleucel was very refractory to multiple prior lines of therapy. On average, these patients had progressed on 3 or more lines of therapy before they received infusions with the drug.

The production of this anti-CD19 CAR T-cell product is different from the others. Although brexucabtagene autoleucel and axi-cel are created by the same manufacturer, the lymphocytes are selected out and then the vector transduces the DNA moiety into the T cell. The reason behind this is because there is some concern around circulating mantle cells; you don’t want to transduce those.

Overall, this [product was examined in] a very heavily pretreated population and we saw about 62% of them achieve a CR, which led to the approval in this disease. More studies will be done to confirm those findings, but this is an exciting way to treat patients with MCL.

You also mentioned liso-cel, which is under investigation in relapsed/refractory DLBCL. How does the toxicity of this product compare with the other therapies discussed?

Liso-cel was the third product to be investigated in DLBCL. To date, we see a significantly lower incidence of cytokine release syndrome (CRS) along with similar response and CR rates. It’s important to remember that, since this was one of the later products to emerge in the clinical setting, many centers already had experience with managing CAR T-cell–associated toxicity. As such, better management and more experience could be why we’re seeing lower toxicity.

In addition, with tisagenlecleucel and axi-cel we have data showing that early intervention to prevent CRS or other toxicity from becoming too severe does not appear to impact the long-term effectiveness.

With liso-cel, CD4 and CD8 are infused one after the other; this is what makes it different from the other [products] and this is thought to effect CRS and neurotoxicity. Many of these patients were infused with CAR T cells in the outpatient setting. This could be another way to administer this therapy in the future as centers gain more experience.

What are some of the anti-BCMA approaches under investigation?

Anti-BCMA CAR T-cell products [have also emerged]. We are hoping that, within the next year, idecabtagene vicleucel (ide-cel; bb2121) will receive regulatory approval in multiple myeloma. [With this product, we have seen that] about 90% to 100% of the patients respond to this CAR T-cell therapy. It’s important to remember that, even patients who achieved minimal residual disease negativity with the CAR T-cell therapy, still experienced a median PFS of around 18 months. This is not a cure; patients will still relapse. However, using these approaches in earlier lines of treatment might improve outcomes.

We then discussed data from a Legend Biotech study that was initially conducted in China. With long-term follow-up of around 30 months, we saw a durability of response in some patients, especially if they achieved a CR with the anti-BCMA CAR T-cell therapy. Conversely, patients who don't achieve a CR seem to have earlier relapses. Notably, the same product has been licensed by Johnson and Johnson in the United States; the study examining it use is currently ongoing. The initial report was presented at the 2019 ASH Annual Meeting and showed that almost 100% of patients responded to the treatment. Again, we must wait for longer-term follow-up data to better understand the durability of these responses.

What are some of the real-world data that have read out with these products?

Compared with what was seen in the clinical trial setting, [we have seen that even] with short follow-up, the results appear to be similar to the results reported from the initial registration trials. Surprisingly, data were presented during the 2019 ASH Meeting and showed that the response rates in patients who were treated in the United Kingdom with both of the anti-CD19 CAR T-cell products was lower than what we would expect to see in the United States.

Notably, the [process] for [receiving] CAR T-cell therapies in the United Kingdom differs from that used in the United States. [Patients] must receive approval from a panel, and this approval process takes some time. With this said, some patients may have disease that has progressed more rapidly, and they might not have been the appropriate candidates during that time for a CAR-T cell study. In future research, we will need more patients and longer follow-up data to truly see what happens.

What challenges have the real-world findings revealed?

In the real-world setting, we currently experience some challenges in terms of acquiring access to this treatment in many patient populations. Sometimes this is due to insurance authorization and reimbursement issues. On the clinical side, we are seeing that, by the time patients get referred, go through the insurance authorization process, the T cells get collected, and they go through the 2-3 week period during the manufacturing process, some of these patients might experience disease progression. As such, it has been proposed that the use of additional bridging therapy may be important in the real-world setting.

Although there are not much data on how many patients had bridging therapy used, it seems like patients who are able to get to CAR T-cell therapy after the approval seem to have good responses, irrespective of age. Axi-cel was examined in patients who were older and younger than 65 and the responses were found to be very similar.

Ultimately, we need to gain more access to this therapy. To do that, we need to improve the insurance approval algorithm so that patients can receive treatment in a timelier manner. DLBCL is a disease that is commonly found in older patients [and they appear] to derive similar benefits [to their younger counterparts]. Hopefully, the Centers for Medicare & Medicaid Services will continue to reimburse this modality at a rate that hospitals will be able to provide this therapy for patients.

Are there any additional approaches under investigation that you wanted to highlight?

We are looking to better define the mechanism of resistance. If you look at the CR rates in DLBCL, most studies report overall response rates around 50% to 80% and CR rates around 40% to 50%. We are now trying to determine who the patients are that experience a response but do not achieve CR. One approach is to biopsy at the time of relapse. PD-1 and PD-L1 also appear to play a role; to this end, investigators are also looking at using checkpoint inhibitors after relapse to see whether that can help patients get back into remission.

Another promising therapy is the molecule that's been created to target CD20 and CD19. This might help reactivate some of the anti-CD19 CAR T-cells, rather than having to make and infuse new ones. If patients lose the CD19 expression, targeting CD20 and having the back end activate the CAR T cells again so that the disease cells can be targeted again, is an exciting approach. Hopefully, in future research, we'll continue to find more ways to overcome resistance in this space.

What are the next steps for research with this modality?

Novel ways to improve CAR T-cell therapy outcomes are being examined. [Ways to overcome] mechanisms of resistance, for example, are under evaluation. To this end, [investigators are looking into] using a dual-targeting approach with CD19 and CD20, or CD19 and CD22 bispecific CAR T cells. In a disease like ALL, there has been the development of a CD19/CD20 bispecific antibody, which appears to help patients who develop resistance to CD19 CAR T cells.

[We are also looking into] mechanisms to prevent BCMA from becoming soluble so that we can improve outcomes for patients in terms of BCMA-targeted therapy. Another interesting concept that was discussed at the 2019 ASH Annual Meeting was looking at CAR T cells, which can be coupled with any specific antibody to activate T cells and then infuse them. That might be something to examine in the future: Using CAR T cells with antibodies to help target more cancers.