Background: In clinical trials, the expansion and persistence of CAR-T cells correlate with therapeutic efficacy. However, properties of CAR-T cells that enable their in vivo proliferation have still to be consistently defined and the role of CAR-T bag content has never been investigated in a real life setting. Experimental Design: Residual cells obtained after washing 61 anti-CD19 CAR-T product bags were analysed to identify tisagenlecleucel/Tisa-cel and axicabtagene ciloleucel/Axi-cel phenotypic features associated with post-infusion CAR-T cell in vivo expansion and with response and survival. Results: While Tisa-cel was characterized by a significant enrichment in CAR+CD4+ T cells with central memory (P<0.005) and effector (P<0.005) phenotypes and lower rates of CAR+CD8+ with effector memory (P<0.005) and naive-like (P<0.05) phenotypes as compared to Axi-cel, the two products displayed similar expansion kinetics. In vivo CAR-T cell expansion was influenced by the presence of CAR-T with a CD8+ T central memory signature (P<0.005) in both Tisa-cel and Axi-cel infusion products and was positively associated with response and progression-free survival (P<0.05). Conclusions: Our data indicate that despite the great heterogeneity of Tisa-cel and Axi-cel products, the differentiation status of the infused cells mediates CAR-T cell in vivo proliferation that is necessary for anti tumor response.

Infections are a major cause of morbidity and mortality during neutropenia after chemo-radio therapy and hematopoietic stem cell transplantation (HSCT). The use of low-microbial Protective-Diet (PD) in the peri-transplant period is a standard of care despite its efficacy has never been tested prospectively. We conducted a multicenter, randomized, non-inferiority trial enrolling all consecutive adult patients undergoing high-dose-induction chemotherapy or HSCT with the objective to compare Non-Restrictive-Diet (NRD) versus PD. Overall, 222 patients were enrolled, randomized, and analyzed. One hundred and seventy-five (79%) subjects received autologous-HSCT, 41(18%) received allogeneic-HSCT while 6(3%) patients received high-dose-induction chemotherapy. There was no significant difference in terms of incidence of Grade≥2 infections and death during neutropenia in the two arms (65% in PD vs 61% in NRD patients,RR=1.0;95%CI=0.9-1.3,p=0.7). In multivariable analysis, only multiple myeloma diagnosis, fluoroquinolone prophylaxis and absence of mucositis were associated with lower incidence of Grade≥2 infections. We did not report any significant variation in terms of hospitalization length, incidence of mucositis and gastrointestinal infections, body weight and serum albumin variations in the two arms. In allogeneic-HSCT recipients, the incidence of acute Graft Versus Host Disease (aGVHD) grade≥3 was similar (20% in PD vs 9.5% in NRD, p=0.4;RR=2.1,95%CI=0.5-9.1,p=0.4). NRD was associated with higher patients' satisfaction (16% in PD vs 35% in NRD, RR=0.5;95%CI= 0.3-0.8;p=0.003). In conclusion Non-Restrictive diet is non-inferior to traditional Protective diet during neutropenia after HSCT, our results demonstrated that implementing a restrictive diet unnecessary burdens patients' quality of life.

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<div>AbstractPurpose:<p>In clinical trials, the expansion and persistence of chimeric antigen receptor (CAR) T cells correlate with therapeutic efficacy. However, properties of CAR T cells that enable their <i>in vivo</i> proliferation have still to be consistently defined and the role of CAR T bag content has never been investigated in a real-life setting.</p>Experimental Design:<p>Residual cells obtained after washing 61 anti-CD19 CAR T product bags were analyzed to identify tisagenlecleucel/Tisa-cel and axicabtagene ciloleucel/Axi-cel phenotypic features associated with postinfusion CAR T-cell <i>in vivo</i> expansion and with response and survival.</p>Results:<p>While Tisa-cel was characterized by a significant enrichment in CAR⁺CD4⁺ T cells with central memory (<i>P</i> < 0.005) and effector (<i>P</i> < 0.005) phenotypes and lower rates of CAR⁺CD8⁺ with effector memory (<i>P</i> < 0.005) and naïve-like (<i>P</i> < 0.05) phenotypes as compared with Axi-cel, the two products displayed similar expansion kinetics. <i>In vivo</i> CAR T-cell expansion was influenced by the presence of CAR T with a CD8⁺ T central memory signature (<i>P</i> < 0.005) in both Tisa-cel and Axi-cel infusion products and was positively associated with response and progression-free survival (<i>P</i> < 0.05).</p>Conclusions:<p>Our data indicate that despite the great heterogeneity of Tisa-cel and Axi-cel products, the differentiation status of the infused cells mediates CAR T-cell <i>in vivo</i> proliferation that is necessary for antitumor response.</p></div>

<div>AbstractPurpose:<p>In clinical trials, the expansion and persistence of chimeric antigen receptor (CAR) T cells correlate with therapeutic efficacy. However, properties of CAR T cells that enable their <i>in vivo</i> proliferation have still to be consistently defined and the role of CAR T bag content has never been investigated in a real-life setting.</p>Experimental Design:<p>Residual cells obtained after washing 61 anti-CD19 CAR T product bags were analyzed to identify tisagenlecleucel/Tisa-cel and axicabtagene ciloleucel/Axi-cel phenotypic features associated with postinfusion CAR T-cell <i>in vivo</i> expansion and with response and survival.</p>Results:<p>While Tisa-cel was characterized by a significant enrichment in CAR⁺CD4⁺ T cells with central memory (<i>P</i> < 0.005) and effector (<i>P</i> < 0.005) phenotypes and lower rates of CAR⁺CD8⁺ with effector memory (<i>P</i> < 0.005) and naïve-like (<i>P</i> < 0.05) phenotypes as compared with Axi-cel, the two products displayed similar expansion kinetics. <i>In vivo</i> CAR T-cell expansion was influenced by the presence of CAR T with a CD8⁺ T central memory signature (<i>P</i> < 0.005) in both Tisa-cel and Axi-cel infusion products and was positively associated with response and progression-free survival (<i>P</i> < 0.05).</p>Conclusions:<p>Our data indicate that despite the great heterogeneity of Tisa-cel and Axi-cel products, the differentiation status of the infused cells mediates CAR T-cell <i>in vivo</i> proliferation that is necessary for antitumor response.</p></div>