After breakthroughs in the treatment of refractory B-cell neoplasms, CAR T cell therapies became the new beacons of hope in oncology, with raising numbers of clinical trials each year. However, HIV-positive patients are frequently excluded from clinical studies and/or therapies despite their elevated risk of developing cancer. Therefore, we aim at developing a GMP manufacturing process for CAR T cell therapies in combination with knockout of the HIV co-receptor C-C motif chemokine receptor 5 (CCR5), to protect those cells from de novo HIV infection. Our lab recently developed a GMP-compatible mRNA electroporation protocol for the automated production of CCR5-edited CD4⁺-T cells via our optimised CCR5-targeting TALE nuclease, CCR5-Uco-hetTALEN, in the closed CliniMACS Prodigy system. The automated T Cell Engineering (TCE) process reliably produced high numbers of viable CCR5-edited CD4⁺-T cells (1.65 - 5.00×10⁹ cells with >60% CCR5 editing) within 12 days. Notably, about 40% of total large-scale produced cells showed a biallelic CCR5 editing with low (< 2 %) CCR2 off-target activity reducing the risk of chromosomal aberrations; between 25 - 42% of produced cells had a central memory T-cell phenotype. Moreover, we successfully produced up to 9.2x10⁸ CD19-CAR T cells at the CliniMACS Prodigy using lentiviral transduction. Additionally, we currently test different antiretroviral substances to be used in our combined process to produce CCR5-edited CD19-CAR T cells for HIV patients. In conclusion, we are currently establishing a GMP-compatible manufacturing protocol of protected CCR5-negative CAR T cells for the treatment of HIV-positive cancer patients.