This novel next-generation autologous, mesothelin-targeted CAR T therapy was developed in collaboration with researchers at MSK, Dr. Prasad Adusumilli, who led two trials with first-generation mesothelin CAR T therapy and engineered T-cell intrinsic checkpoint blockade by PD1DNR to overcome the immune suppression of PDL1, and Dr. Michel Sadelain, a leader in the CAR T-cell field who developed the 1XX co-stimulatory domain technology to extend T-cell effector function while limiting cell exhaustion.
At the 2020 American Association for Cancer Research Virtual annual meeting II, preclinical data were presented from ATA2271 IND-enabling studies conducted collaboratively in Dr. Adusumilli's laboratory, showing the effects of combining multiple novel technologies in this next-gen CAR T therapy, which includes both 1XX co-stimulatory domain signaling and an engineered PD1DNR.
ATA2271 was associated with less cell exhaustion, improvements in functional persistence, serial cell killing, and enhanced in vivo efficacy when compared with first-generation mesothelin CAR T therapy.
These effects were maintained through multiple redosings with ATA2271 and are consistent with emerging views in the field regarding preferred characteristics of CAR Ts when targeting solid tumors, including mesothelioma.
This improved profile of ATA2271 will now be assessed in a Ph1 clinical trial led by principal investigator, Dr. Roisin O'Cearbhaill.
Although CAR T cell therapies have been approved for certain hematologic malignancies, they have not yet proven effective in solid tumor settings.
Mesothelin is a tumor-specific antigen that is commonly expressed at high levels on the cell surface in many aggressive solid tumors including mesothelioma, ovarian cancer, pancreatic cancer, and non-small cell lung cancer.
Atara has selected mesothelin as the target for both the ATA2271 autologous and the ATA3271 allogeneic programs along with novel CAR T-cell technologies that have the potential to further enhance activity and resulting clinical benefits.
ATA3271, the allogeneic version of this CAR T, leverages Atara's EBV T-cell platform and is currently in IND-enabling studies.
In collaboration with MSK, Atara is developing ATA2271, a next-generation autologous mesothelin-targeted CAR T using novel 1XX CAR signaling and programmed death-1 dominant negative receptor (PD1DNR) checkpoint inhibition technologies (M28z1XX PD1DNR CAR T cells).
This technology is supported by the safety and anti-tumor efficacy that was exhibited in prior studies evaluating a mesothelin-directed CAR utilizing a CD28 co-stimulatory signaling domain.
This autologous mesothelin-targeted construct (using M28z CAR T cells) combined with PD-1 antibody is being studied in two ongoing MSK Phase 1 studies in patients with malignant pleural disease and mesothelioma, non-small cell lung cancer, and breast cancer (NCT02414269 and NCT02792114).
Michel Sadelain, MD, Ph.D., director, Center for Cell Engineering, and Head, Gene Expression and Gene Transfer Laboratory at MSK and Prasad Adusumilli, MD, Deputy Chief of Thoracic Service, vice chair of Department of Surgery, and Head Solid Tumors, Cell Therapy, Cellular Therapeutics Center at MSK have intellectual property interests in technology licensed by Memorial Sloan Kettering to Atara, related to this program.
Dr. Adusumilli also has compensated consulting relationships with Atara. MSK has institutional financial interests related to Atara in the form of intellectual property rights and associated interests by virtue of licensing agreements between MSK and Atara.
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