Region 3: Immune and Cellular Tx, Part II – MedPage Today

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CAR-T in Hematologic Cancers

Targeting cancer via immunomodulation has been the holy grail of oncology. Over the last few years, the hottest topic in hematology has been chimeric antigen receptor (CAR) T-cell therapy, or CAR-T.

To discuss the development of CAR T-cell therapy, one must look back at the fascinating history of Carl June, MD. In the 1980s, when so many Americans were partying like it was 1999, June began his journey to become an oncologist. Researchers had learned that in patients with an identical twin, leukemia could be cured via high-dose chemotherapy followed by a bone marrow transplant. But most patients didn't have a twin, so hematologists had to identify a best match. Given their different immune systems, patients began experiencing graft-versus-host disease.

June began working on a way to achieve the same benefits of a transplant, without the transplant. His approach, using patients' own immune systems, took much teamwork and about 30 years to develop.

To hear June share his memories is fascinating. Given that he was in the Navy, he learned about radiation-induced bone marrow failure from victims of Chernobyl. The Navy wanted to learn how to replenish immune systems post-radiation exposure, so he set about doing this.

As geopolitical pressures changed and the likelihood of nuclear war decreased, June and his team shifted their focus to rebuilding T-cell populations in patients with HIV and AIDS. They harvested T cells from patients, amplified them, and infused them back into patients. He recalls being shocked that it worked!

In 1999, June joined the faculty of the University of Pennsylvania and resumed studying leukemia, now applying his work in HIV to the care of cancer patients. The first cancer patient was treated with CAR T-cell therapy in 2010 and the treatment ultimately led to the 2017 FDA approval of tisagenlecleucel (Kymriah) for pediatric acute lymphoblastic leukemia (ALL). A year later tisagenlecleucel gained approval for adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

Adverse events associated with this therapy are significant and include cytokine release syndrome (CRS) and neurologic toxicity.

CRS occurs after infusion and may include high fever, hypotension, and other serious hemodynamic changes. Fever occurs as tumor cells are being killed, and larger tumor volumes can yield higher fevers. CRS can be managed with agents that block the effects of interleukin-6, like tocilizumab (Actemra), and/or corticosteroids.

Neurotoxicity from CAR-T is now described as immune effector cell-associated neurotoxicity syndrome, and is characterized by global encephalopathy, aphasia, seizures or seizure-like activity, obtundation, tremor, myoclonus, and hallucinations. It is almost always reversible.

In addition to tisagenlecleucel, another CAR T-cell product, axicabtagene ciloleucel (Yescarta) is approved for certain types of non-Hodgkin's lymphoma. These therapies can only be administered by authorized clinicians.

If patients are considered to be candidates for CAR T-cell therapy, they have T cells harvested via leukapheresis. They undergo engineering so that they express CARs on their surface, then are multiplied. This process is estimated to take 8 to 12 days. When ready, they are infused back into the individual. Some patients will have cytoreductive chemotherapy prior to infusion. After infusion, patients remain in the hospital for close monitoring. The first month is critical in the process of recovery. Once injected into the patient, the CAR T cells expand from 1,000- to more than 10,000-fold. This expansion peaks at 10 to 14 days and coincides with the onset of CRS.

Results from ELIANA, a phase II trial of tisagenlecleucel in pediatric and young adult patients with CD19-positive relapsed or refractory B-cell ALL, demonstrated an overall remission rate of 81% at 3 months. Moreover, rates of event-free survival and overall survival (OS) were 73% and 90%, respectively, at 6 months and 50% and 76% at 1 year. CRS occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care. Long-term follow-up from the trial showed that two-thirds of those who attained complete responses remained in remission at 18 months.

In the JULIET trial, tisagenlecleucel was given to adult patients with relapsed or refractory DLBCL who were ineligible for or had disease progression after autologous stem cell transplant. Infusions were given to 93 patients and the therapy yielded an overall response rate of 52%, with complete responses in 40% and partial responses in 12%. At 12 months after initial response, the rate of relapse-free survival was 65%, and nearly 80% in those who achieved a complete response. The most common grade 3/4 adverse events of special interest included CRS (22%), neurologic events (12%), cytopenias lasting more than 28 days (32%), infections (20%), and febrile neutropenia (14%). Three patients died from disease progression within 30 days after infusion.

In the ZUMA-1 trial, treatment with axicabtagene ciloleucel led to a response rate of 82% among 101 patients with refractory DLBCL, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma. In all, 54% had a complete response. With a median follow-up of 15.4 months, 42% of the patients had maintained their response, including 40% of complete responders. Half of the patients remained alive at 18 months. The most common adverse events of grade 3 or higher were neutropenia in 78%, anemia in 43%, and thrombocytopenia in 38%. Grade 3 or higher CRS and neurologic events occurred in 13% and 28%, respectively. Three patients died during treatment.

At the recent American Society of Hematology (ASH) annual meeting, data from the phase I LEGEND-2 trial was presented to much enthusiasm. LCAR-B38M, a newer CAR T-cell therapy, was given to 57 individuals with relapsed/refractory multiple myeloma, leading to a response rate of 88%, with complete responses in 74%. Median duration of response was 22 months, and the 18-month OS rate reached 68%.

There are multiple ongoing trials using the FDA-approved compounds in other settings. Additional therapies are under investigation, and next-generation "smarter" CAR-T products are being developed. Those that address multiple targets will be prioritized. Hopefully, manufacturing and production will also be streamlined.

'Off the Shelf' Cellular Therapy

Despite the excitement surrounding CAR-T therapies, there have been concerns as well. These are patient-specific, personalized therapies that require waiting periods while the product is created. With traditional CAR T-cell therapy, patients must be well enough for cell collection and remain clinically stable for approximately 1 month before cells can be made and re-infused. It is estimated that about one-third of patients enrolled in CAR-T trials never make it to infusion due to the severity of their illness. Patients must also have an adequate supply of T cells to start with.

The nature of this personalized therapy means that there is a lot of work involved, along with the potential for human error. Associated costs are also very high, with estimates for the currently available products ranging from $370,000 to just shy of $500,000. This excludes costs of administration and costs related to prolonged hospitalizations due to adverse events.

Given the challenges of CAR-T therapy, clinical investigators are working to create a next generation of cellular therapies known as "off-the-shelf" treatments that can originate via a healthy donor's cells, and then be mass-produced and used for multiple patients -- so-called universal CAR T cells.

Multiple collaborators have active open-label, single-arm phase I trials for an off-the-shelf allogeneic CAR-T product called UCART19.

At ASH 2018, pooled data on 21 patients treated with UCART19 in two phase I trials -- PALL and CALM -- were presented. Of 17 patients who also received fludarabine/cyclophosphamide and an anti-CD52 monoclonal antibody, 82% achieved complete remission. In four patients who only received UCART19 and fludarabine/cyclophosphamide, no responses were observed and there was minimal UCART19 expansion. Safety was encouraging, as only two cases of low-grade graft-versus-host disease were seen, and neurotoxicity and CRS were as expected and manageable.

More recently, data from a large phase I study presented at the ASH 2019 meeting showed that 46% of 191 patients with relapsed, difficult-to-treat non-Hodgkin's lymphoma responded to mosunetuzumab, an investigational bispecific antibody. This included patients who were resistant or refractory to approved CAR T-cell therapies. The new agent, which targets CD3 and CD20, induced objective responses in 37% of patients with aggressive lymphomas and in 63% of those with indolent forms of the disease. In a subgroup of 18 patients with prior CAR-T exposure, seven responded to mosunetuzumab.

Advantages of such "off-the-shelf" therapies include their increased availability, that they eliminate the need for patients to have leukapheresis and the waiting period involved, and they are likely to be less expensive in comparison to traditional CAR-T.

We will likely witness an explosion of these products over the next few years.

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Region 3: Immune and Cellular Tx, Part II - MedPage Today