CAR T Cells Highly Successful in ALL

David Maloney, MD, PhD

Defined composition chimeric antigen receptor (CAR) T cells directed against CD19 have potent anti-tumor activity in B cell malignancies, including acute lymphocytic leukemia (ALL). The experience with CD19 CAR T cells in ALL was addressed by David Maloney, MD, PhD, at the NCCN 12th Annual Congress: Hematologic Malignancies in San Francisco.

“A CAR is essentially using an antibody to redirect the T cell to attack whatever the antigen that the antibody is specific for,” said Maloney, member of the Clinical Research Division, Fred Hutchinson Cancer Research Center in Seattle. “The second-generation CARs is where all the action is.” They are usually directed against CD19, CD20, or CD22 (Maloney focused his talk on CARs directed against CD19). The target is key in the success of these treatments.

“They’re linked to a transmembrane domain of the T cell receptor and have a signaling domain from either CD28 or 4-1BB,” he said. “This greatly improves the recognition and the killing of tumor cells and has led to the explosion of these new therapies.”

His group at Fred Hutchinson has treated >200 patients with relapsed/refractory B-cell malignancies.¹ In a preclinical model, the combination of CD8-derived CAR T cells and CD4-derived CAR T cells provided optimal potency. They were able to make CAR T cells in 100% of patients. In the 36 patients with heavily pretreated ALL, the CAR T cell product was manufactured to the target dose for all patients, and 33 of 36 (92%) had products formulated in the defined composition. Outpatient delivery of lymphodepletion and CAR T-cell infusion was possible in 26 of the 36 (72%).

The rate of complete response (CR) was 94% and the molecular CR rate by high resolution flow cytometry was also 94%.² “Even in patients with massive extramedullary disease, most of these patients [6 of 7] will achieve a complete remission,” he said.

Two lessons learned from the protocol is that higher doses of CAR T cells of defined composition result in an earlier and higher peak of CAR T cell proliferation in blood and the peak of CAR T cell expansion is greater in patients with higher bone marrow tumor burden.² Also, adding fludarabine to cyclophosphamide improves CAR T cell persistence, translating into improved rates of disease-free survival (DFS) and overall survival (OS).

Serious toxicity (ie, neurotoxicity and requirement for admission to the intensive care unit) occurs mainly in patients with high tumor burden and robust CAR T cell expansion. “People who get into real trouble could have toxicity very early on,” said Maloney. Levels of interferon-gamma, interleukin-6, ferritin, and C-reactive protein are higher in patients who experience toxicity, but are noted after the fact, he said. A predictive biomarker of serious toxicity that may allow early intervention is serum cytokine level on day 1 after CAR T cell infusion.

“We do risk-adaptive dosing of CAR T cell dosing,” he said. The more marrow blasts you have, the fewer CAR T cells we give. We actually give more T cells to less disease. This has led to a reduced incidence of toxicity.”

The main toxicities are cytokine release syndrome (CRS) and neurotoxicity. CRS responds rapidly to tocilizumab (Actemra) and dexamethasone. “Patients can have fevers of 105 and be hypothermic within hours,” he said. Neurotoxicity presents later (onset often 2 to 4 days after CRS), often manifests as word finding difficulties, and can progress to coma. It may be associated with cerebral edema or seizures. It is generally reversible. Whether treatments aimed at treating CRS can prevent neurotoxicity is not clear.

The Memorial Sloan Kettering Cancer Center experience with CAR T 19-28zeta in patients with adult ALL is similar to that at Fred Hutchinson.³ The CR rate in the 31 patients with >5% marrow blasts was 77% and in those with <5% marrow blasts the CR rate was 95%.

Monoclonal antibodies

Among the first 50 patients enrolled in the ELIANA phase 2 trial of tisagenlecleucel (Kymriah), in which pediatric patients were studied, the CR/CRi rate was 82% at 3 months after the first infusion.⁴ Six-month OS was 89% and the 6-month DFS was 60%. There were two deaths in the first 30 days after infusion, one from ALL and one from cerebral hemorrhage. The rate of CRS was 79%, occurring at a median of 3 days. Based on these data, tisagenlecleucel was approved in August 2017 for use in patients up to 25 years old.Maloney also described recent findings with the monoclonal antibodies rituximab (Rituxan), inotuzumab ozogamicin (Besponsa), and blinatumomab (Blincyto).

Rituximab added to chemotherapy produced modest improvement with minimal toxicity in adult patients with CD20-positive Philadelphia chromosome-negative ALL compared with chemotherapy, with improved event-free survival and a trend toward improved OS and more rapid cleating of minimal residual disease.⁵ Fewer allergic reactions to asparaginase were observed in the rituximab group. Although not approved specifically for the treatment of ALL, rituximab “is certainly a reasonable approach,” said Maloney.

Inotuzumab ozogamicin improved the rate of CR, the duration of remission, and progression-free survival (PFS), as well as OS, compared with standard of care chemotherapy in a randomized trial of patients with relapsed/refractory ALL, but with a high rate of veno-occlusive disease in patients with prior or subsequent stem cell transplant.⁶ However, a minority of patients was still in remission by 12 months and PFS dropped rapidly, Maloney noted, and at 2 years, the rate of event-free survival was only 20 to 25%.

Blinatumomab resulted in significantly longer OS in a randomized comparison with chemotherapy in patients with relapsed/refractory B-cell precursor ALL, but delivery is cumbersome (4-week continuous infusion).⁷ Blinatumomab was more effective in patients with lower disease burden. As with the other monoclonal antibodies, “although it is significant, it is not curing the vast majority of our patients, and the OS when you get out to 1 and 2 years is quite low,” he said.

References

1. Sommermeyer D, Hudecek M, Kosasih PL, et al. Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia 2016;30:492-500.
2. Turtle CJ, Hanafi LA, Berger C, et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest 2016;126:2123-38.
3. Park JH, Riviere I, Wang X, et al. Impact of disease burden on long-term outcome of 19-28z CAR modified T cells in adult patients with relapsed, refractory B-cell ALL. J Clin Oncol 34, 2016 (suppl):Abstract 7003.
4. Grupp SA, Laetsch TW, Buechner J, et al. Analysis of a global registration trial of the efficacy and safety of CTL019 in pediatric and young adults with relapsed/refractory acute lymphoblastic leukemia. 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 221.
5. Maury S, Chevret S, Thomas X, et al. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med 2016;375:1044-53.
6. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med 2016;375:740-53.
7. Kantarjian HM, Stein A, Gökbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 2017;376:836-47.