Integration of Cellular Therapy Jumpstarts Research Efforts in Acute Leukemias

Michael Grunwald, MD

With the goal of capitalizing on the efficacy observed with cellular therapies in acute leukemias, ongoing research efforts are underway to address unanswered questions regarding the role of transplant in conjunction with cellular therapy, optimal toxicity management, antigen escape, and methods to overcome myelosuppression and immunosuppression in these diseases, said Michael Grunwald, MD.

“Our ability to use cellular therapies to treat acute leukemias is expanding,” said Grunwald. “We have new non-transplant therapies coming along, some [of which] might be used as adjuncts to transplant rather than independently. For example, [natural killer (NK)] cells are being investigated in conjunction with transplant.”

“CAR T-cell therapies are further along in lymphoma vs leukemia and are further along in B-cell acute lymphoblastic leukemia [ALL] vs acute myeloid leukemia [AML],” Grunwald added. “However, seeing the efficacy [of these products] in ALL and now a possible efficacy signal or proof-of-principle in AML is very encouraging that we might be able to get more efficacy and less toxicity with some tweaking of our methods over time.”

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on CAR T-cell therapy, Grunwald, a clinical assistant professor of medicine at the University of North Carolina and a hematologist/oncologist at the Levine Cancer Institute of Atrium Health, discussed the evolving landscape of cellular therapy in acute leukemias and key research efforts and hypotheses aimed at addressing ongoing challenges.

OncLive^®: How could NK-based and cytokine-induced killer cellular therapies work in conjunction with transplant to prevent relapse in acute leukemia?

Grunwald: Therapies [with] NK cells have been around for a long time, but there hasn’t been a way to show consistent efficacy for this technology in treating [patients with] acute leukemias. However, some encouraging data have emerged from [The University of Texas MD Anderson Cancer Center] using NK cells in conjunction with haploidentical transplant as a way to prevent relapse. The NK cells are infused before and after transplant to try to increase the efficacy against leukemia while not causing additional graft-vs-host disease [GVHD].

In a relatively small number of patients, the overall survival and the progression-free survival [data] have been very encouraging. I’d like to see an expanded number of patients treated in this manner with NK cells in the peritransplant setting to try to prevent relapse and enhance the efficacy of transplant.

It is important to mention that in these instances, the NK cells are coming from the donor for the transplant, and they are given in a way to try to augment the effect of transplant.

Beyond NK-based therapies, what other research efforts are ongoing to try to prevent relapse in acute leukemias?

Many efforts [are underway] to prevent relapse in myeloid and lymphoid malignancies after allogeneic transplant. A lot of these incorporate targeted therapies after transplant. For example, in patients with FLT3 mutations or patients whose leukemia harbors a Philadelphia chromosome, we oftentimes add on a targeted inhibitor after transplant. However, no prospective study has shown an advantage for a targeted inhibitor after transplant.

A study is ongoing in FLT3-mutated patients looking at gilteritinib [Xospata] vs placebo after transplant. It will be interesting to see what the results of that study show.

A new therapy [called] CC-486 or oral azacitidine [Vidaza] can be administered as maintenance therapy after chemotherapy for patients with AML. That [agent] is being tested in the posttransplant setting, but we don’t have results that confirm efficacy in that setting [yet].

Finally, we have IDH1/2 inhibitors and more general therapies under investigation after transplant using the same ideas that we use before transplant to try to retain a remission.

The cellular therapy approach with NK cells is exciting because it might allow us to harbor some of the benefits of immunotherapy without adding additional risk of GVHD.

How has the integration of tisagenlecleucel (Kymriah) affected the ALL treatment paradigm?

It’s been very exciting to have a CAR T-cell therapy available for ALL. Unfortunately, right now, this agent is only approved in younger patients up to the age of 25. So, until [a patient’s] 26th birthday, they could qualify for tisagenlecleucel for relapsed/refractory ALL.

Further studies of this agent and similar agents in the older ALL population will be important because we need more options to treat such patients. For the younger patients, having this available has been a game changer because it can get patients back into a sometimes very durable remission following relapse.

How has CAR T-cell therapy affected the role of transplant in this disease?

The jury is still out. Many patients who received tisagenlecleucel have already undergone transplant and relapsed. They might have a durable remission with CAR T-cell therapy, but there is still the risk of relapse via various mechanisms. The question is: Should a patient have a second transplant at that point in time or, if they haven’t yet had a transplant, should they have one to try to turn their remission into cure?

We don’t have a great sense of the proportion of patients in which tisagenlecleucel itself might be a [curative therapy], but there is some fear that it is probably not curative for most patients. Therefore, to consolidate the therapy with transplant might make sense for the majority of patients with relapsed/refractory disease provided they could tolerate transplant at that point in time.

We are able to get more patients to transplant with better pretransplant therapies. We are able to transplant more patients, and older patients, because we have more donors available now with the common acceptance of haploidentical donors as a reasonable option for patients. We also have better supportive care, which has expanded transplant to some older patients who are fit. The age of patients in whom we transplant for leukemia has increased over time. All of this is very exciting.

In what patients would you consider transplant after CAR T-cell therapy?

If a patient had a shorter remission or had refractory disease to begin with, I want to be more aggressive with transplant. If a patient had minimal residual disease after receiving therapy with CAR T cells, then I am likely to pursue transplant. Patient preferences come to mind as well because transplant carries significant risks. Transplant also does carry a higher chance of cure than other therapies. Balancing the benefits and risks is a patient-specific conversation that requires the team of care providers, the patient, and [the patient’s] family.

What data have been observed with 19-28z CAR T-cell therapy in B-cell ALL?

[19-28z CAR T-cell therapy] was [evaluated] in a heavily pretreated group of adult patients. Patients were aged 23 to 74 years and the median age was 44 years, so [this was] an older group of patients compared with [data with tisagenlecleucel].

About 36% of these patients had received prior transplant, and 25% had received prior blinatumomab [Blincyto]. A lot of the novel therapies and immune-based therapies had already been used in these patients.

What was remarkable to me was that 83% of patients were able to achieve a complete remission. Some tweaks were made to the study as it was going on to try to reduce toxicities, such as cytokine release syndrome [CRS]. We are learning how to dose the cells and fractionate doses of cells to reduce the toxicity of CAR T cells in adults, but the efficacy was so convincing that this is an area that requires further exploration in adults with ALL.

What strategies are underway to address ongoing challenges with CAR T-cell therapy in B-cell ALL?

A number of challenges [are being faced in] the ongoing development of CAR T-cell therapies in B-cell ALL, [most notably] is CRS and neurotoxicity. One innovative way of trying to overcome these toxicities is with the use of on and off switches. These are genes and consequent proteins that are incorporated into the CAR T cells where a patient could be given a drug that would turn off the CAR T cell and shut off toxicity. This has been shown in small groups of patients to be a feasible and efficacious technique. A recent paper in Blood by [Matthew Foster, MD, of the University of North Carolina Lineberger Comprehensive Cancer Center] showed this can be used to reduce rates of neurotoxicity.

Also, we are getting better at using tocilizumab [Actemra] and steroids to treat early signs and symptoms of toxicity. We are trying to see whether we can adjust the conditioning chemotherapy regimen that is given before CAR T cells are infused to try to reduce the risk of CRS and neurotoxicity.

The idea of giving smaller doses of cells in multiple doses might be a way to give the same efficacy with less toxicity compared with giving a large bolus of CAR T cells at once.

Also, the idea of antigen escape [is challenging]. In B-cell ALL, the most far along antigen that CAR T-cell [therapies] are targeting is CD19. If we have that antigen on the surface of the cancer and we are trying to target it, sometimes that antigen will no longer be present on the tumor after the patients receive some treatment. The cancer can continue to grow and progress because [the cells] have lost the antigen that the treatment is targeting.

In this situation, one strategy that has been tried is low-dose radiation, which might turn out to be helpful. The idea of using multiple CAR T-cell constructs at once in a mixed bag might be helpful in this situation. Also, the idea of a single CAR T-cell construct that is targeting 2 or more different antigens [is intriguing] so that we aren’t completely relying on the anti-CD19 activity in this instance to treat [patients with] B-cell ALL.

Finally, T-cell persistence has been challenging. If T cells are not persistently active in the tumor for long enough, that can be a problem. Various adaptations are under way to try to overcome that [including] altering the CAR structure, using humanized CARs, changing the phenotype of CARs, and strengthening CARs or causing them to be more persistent by exposing them to viral antigens.

Some of these methods might help the T-cell activity last longer after they are infused.

Are the challenges faced with CAR T-cell therapy in AML different from those faced in ALL?

[The challenges] are a little bit different [in AML vs ALL]. One [unique] challenge in AML is it seems that the same antigens that are expressed on AML cells are also expressed on normal hematopoietic stem cells or progenitor cells. Eradicating the leukemia often causes myelosuppression when CAR T cells are infused for AML. This is a fear, and also something that seems to be borne out in practice in a small number of patients who have been reported. Here, trying to incorporate the on/off switches again might be helpful because maybe we could turn off the CAR T cells and have less myelosuppression. We could have our hands on the dial a little bit with the use of CAR T-cell therapies in AML.

There is also the idea of editing the allograft and taking out the antigen that we are targeting from the stem cells that are being infused. For example, if one were to use CAR T-cell therapy as a conditioning regimen for an AML transplant, one could then transplant cells that lack the antigen that the CAR T cells are targeting. That would be an innovative way to use this technology, but it is not borne out in practice yet.

We also need to continue to try to identify new antigens. We feel like we know everything when oftentimes we don’t. It is not that long ago that we learned about new mutations that occur commonly in AML, such as the IDH1 and IDH2 mutations. We are always learning more, so perhaps some antigens are expressed in AML cells that are not expressed in normal hematopoietic cells.

Some additional challenges may or may not apply to ALL that apply to AML. For example, AML and prior treatment for AML can prevent T-cell expansion. That particular challenge probably does apply to ALL also. If we were to treat patients earlier in the course with CAR T cells when they have been less exposed to chemotherapy, we might see more efficacy.

We’ve also considered the idea of using allogeneic CAR T-cell therapies. Rather than using a patient’s own cells to produce the CAR T cells, taking somebody else’s CAR T cells to try to induce a remission might be a more helpful way of overcoming this problem. A potential problem with allogeneic cells is GVHD, so trying to attenuate the risk of GVHD will be another challenge to overcome.

Finally, the immunosuppression that exists in AML patients is a challenge because these patients oftentimes have weak immune systems. Trying to increase the ability of the complementary parts of the immune system to work alongside CAR T cells is something that has to be worked on with CAR T-cell therapy in AML.

Are there ongoing research efforts with CAR T-cell therapy in AML that may move the needle forward?

I know this is under investigation in multiple centers, including the University of Pennsylvania and City of Hope. I am looking forward to seeing more data. It is exciting that we have some proof-of-principle with anti-CD123 specific CAR T cells where patients have been able to achieve remission and undergo transplant. This is a relatively small number of patients, simply because not many patients have been treated or reported so far. The fact that we have proof-of-principle here and that we will soon have more data reported from research centers showing slightly larger numbers of patients [is encouraging]. We will have to see what the response rates and toxicities are and how the efficacy and toxicity can be balanced.