Add-On Molecule May Boost CAR T-Cell Activity



NATIONAL HARBOR, Md. -- Chimeric antigen receptor (CAR) T cells "armored" with an anti-PD-1 molecule led to objective responses in 12 of 13 patients with relapsed/refractory non-Hodgkin's lymphoma (NHL) in a preliminary clinical trial.

The overall response rate of 92.3% included complete responses in seven of the 13 patients (53.8%). The therapy was not associated with added or unexpected toxicity beyond that associated with conventional CAR T-cell therapy, Victor Lu, PhD, of Innovative Cellular Therapeutics in Rockville, Maryland, reported here at the Society for Immunotherapy of Cancer meeting.

"This is a product similar to Yescarta (axicabtagene ciloleucel, axi-cel) and Kymriah (tisagenlecleucel), but with a twist," said Lu. "We've coexpressed a dominant-negative (dn) PD-1 molecule within the same T cells. The design is to improve the anti-immune inhibitory effect in cancer tissue."

CAR T-cell therapy has proven highly effective for relapsed/refractory hematologic malignancies. However, factors in the tumor microenvironment can adversely affect CAR T-cell activity, such as upregulation of PD-1 during T-cell activation.

Several strategies exist to overcome PD-L1/L2 inhibitory signaling, but all have limitations, said Lu. Co-administration of CAR T cells and PD-1/L1 antibody is costly and adds to toxicity. In situ secretion of PD-1/L1 antibody achieves inadequate blockade of inhibitor signaling and causes toxicity. Engineered suppression or elimination of PD-1 is difficult to achieve and expensive.

The strategy developed by Lu and colleagues offers an alternative that addresses limitations of other approaches to inhibition of PD-1 signaling. The team incorporated a dnPD-1 molecule into the CAR T-cell construct, along with a CD19-targeting molecule.

As Lu explained, a dn mutation results in a protein that has lost some aspect of functionality but retains a competitive advantage versus the endogenous protein. The altered PD-1 protein expressed by CAR T cells acts as a "decoy receptor" that binds and blocks the PD-L1/L2 inhibitory signal.

"We have developed a cell-intrinsic strategy that counteracts PD-L1-mediated immunosuppression and enhances the efficacy of CAR T-cell therapy," he said.

The rationale for "armored" CAR T cells has support from biopsy analyses involving patients with NHL that relapsed after treatment with anti-CD19 CAR T cells. The analyses showed loss of CD19 expression (T-cell exhaustion) and increased PD-L1 expression. Additionally, preclinical and clinical data have shown that PD-1 inhibition "refuels" CAR T cells after relapse or failure of CAR T-cell therapy for relapsed/refractory NHL.

Laboratory studies comparing conventional anti-CD19 CAR T cells and the armored CAR T-cells confirmed that the armored cells reversed PD-1/L1-induced suppression of the CAR T cells' cytokine expression, rescued the CAR T cells' impaired cytolytic function, and normalized lysis. In vitro studies showed that the dnPD-1 protein protected the engineered CAR T cells from exhaustion, said Lu.

Clinical experience with the armored CAR T cells began with a 13-patient study conducted in China. The cohort consisted of 11 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and two with relapsed/refractory follicular lymphoma. Both of the patients with follicular lymphoma attained complete responses with the dnPD-1 armored CAR T cells, as did five of the patients with DLBCL. Five patients with DLBCL achieved partial responses, and the one remaining patient with DLBCL did not respond to treatment.

The early clinical success has led to global expansion of the clinical development program, focusing on solid tumors, including thyroid, breast, pancreatic, prostate, and colorectal cancers. The trials involve CAR T-cell constructs that incorporate the dnPD-1 molecule but also other molecules to augment the activity of the primary molecule.

In response to a question from the audience, Lu said follow-up is ongoing in all of the patients in the Chinese study, but he provided no additional information about the status of patients who had partial responses. Asked to elaborate on the safety profile of the armored CAR T-cell therapy, Lu said only that investigators hypothesized that the addition of the dnPD-1 molecule would not increase toxicity beyond the usual effects seen with conventional CAR T-cell therapy, and the trial results supported the hypothesis.

The study was supported by Innovative Cellular therapeutics, and Lu is employed by the company.

Vaccine May Boost CAR T-Cell Activity in Solid Tumors



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CAR-T cells given without the vaccine had no effect on tumors, while CAR-T cells given with the vaccine eliminated tumors in 60 percent of the mice. And the manufacturer has announced plans to launch clinical trials in 2018 investigating tisagenlecleucel and other CAR T cells, in the treatment of multiple myeloma, dlbcl after first relapse, and follicular lymphoma, as well as solid tumors (including glioblastoma, advanced ovarian cancer, and mesothelioma). Its important to note the three CARs likely to be approved in lymphoma in the near future, including jcar017, all use the same murine single-chain Fv antibodythat means if a patient rejects one product, she or he is unlikely to respond to the other two. Lonial tadalafil 20 29 : These are still very early days with this therapy. (The "CAR" in CAR-T cell therapy cialis tablet 20mg is for " chimeric antigen receptor.