David Maloney, MD, PhD
Results in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) suggest that chimeric antigen receptor (CAR) T-cell therapy should be used earlier in treatment, possibly after first relapse, said David G. Maloney, MD, PhD. Administration of these products in earlier lines of therapy could improve outcomes and reduce toxicity, he added.
“The most important thing about CAR T-cell technology is that it shouldn't be reserved just for relapsed/refractory patients who have failed everything,” said Maloney, medical director of Immunotherapy with Seattle Cancer Care Alliance. “Performance status is important. Tumor burden is important. If we can catch these patients early, we have a tremendous opportunity to improve outcomes and make the treatment safer.”
Physicians are interested in CAR T-cell therapy and targeted therapy for relapsed/refractory patients because response rates are low and prognosis is poor. The FDA has already approved the CAR T-cell therapy tisagenlecleucel (Kymriah) for children and young adults with B-cell precursor acute lymphoblastic leukemia and adults with diffuse large B-cell lymphoma (DLBCL).
Moreover, axicabtagene ciloleucel (Yescarta) has been approved by the FDA for patients with relapsed/refractory DLBCL, DLBCL arising from follicular lymphoma, large B-cell lymphoma, primary mediastinal large B-cell lymphoma, and high-grade B-cell lymphoma following 2 or more lines of systemic therapy. If lisocabtagene maraleucel (liso-cel) is approved to treat B-cell NHL, clinicians will have 3 CAR T-cell products at their disposal.
“It is a really exciting time in the field,” Maloney said.
In an interview with OncLive
, Maloney reviewed the latest developments with CAR T-cell therapy in patients with NHL.
OncLive: What is the current state of treatment for DLBCL?
: DLBCL is a disease where we obviously try to cure it with chemotherapy and that can be remarkably successful in 60% to 70% of patients, but for those who don't go into complete remission or who relapse, then this becomes a life-threatening problem. Standard of care is salvage chemotherapy and, if you have responsive disease, autologous stem cell transplant. Unfortunately, with better therapies including R-CHOP, as the CORAL study showed, our success with transplant has gotten even lower. Therefore, people are very interested in the targeted therapies.
Thus far, it's been quite disappointing with the addition of new agents to our backbone of chemotherapy such as standard R-CHOP. You can add a bunch of drugs to it based on molecular profiling, and so far, the studies haven't panned out to be big winners. We are still awaiting results from some of these trials, but that's where we stand right now.
In the relapsed/refractory setting, patients were usually treated with palliative intent because we didn't have good options. With the advent of CAR T cells, we now have 2 commercially available products with a third on the way that show exciting response rates and, at least in some cases with 15 months’ follow-up, durable remissions in about 40% of patients.
One of the more exciting presentations recently was the polatuzumab vedotin data in combination with bendamustine/rituximab. That seems to be another salvage or bridging therapy where you might be able to get people into a better response. If that's the case, you might be able to use it as a bridging therapy to get to CAR T cells. There are new exciting molecules on the way.
Is CAR T-cell therapy becoming more widespread?
There are 2 products currently approved: tisagenlecleucel and axicabtagene ciloleucel, both targeting CD19. A third [liso-cel] is on the way. These products are different. They have a CAR, but they have different costimulatory domains; 1 is CD28 and the other 2 are 4-1BB. That does cause some differences in the clinic.
These are autologous products. We collect T cells from the patient, then transduce them with a retrovirus—either a gamma virus or an antivirus. These genetically change the cells to express the CAR; they have all targeted CD19 so far. These cells are then given back to patient after lymphodepleting chemotherapy. These have led to very high response rates—up to 80% in 3 of the large phase II trials that have been done. The results led to FDA approvals for 2 agents.