Chimeric Antigen Receptor T-cell (CART) immunotherapy led to unprecedented responses in patients with refractory/relapsed B-cell non-Hodgkin lymphoma (NHL); nevertheless, two-thirds of patients fail this treatment. Resistance to apoptosis is a key feature of cancer cells that associates with treatment failure. In 87 NHL patients treated with anti-CD19 CART, we found that chromosomal alteration of BCL-2, a critical anti-apoptotic regulator, in lymphoma cells was associated with reduced survival. Therefore, we combined CART19 with the FDA-approved BCL-2-inhibitor, venetoclax, and demonstrated in vivo synergy in venetoclax-sensitive NHL. However, higher venetoclax doses for venetoclax-resistant lymphomas resulted in CART toxicity. To overcome this limitation, we developed venetoclax-resistant CART by overexpressing mutated BCL-2(F104L) which is not recognized by venetoclax. Notably, BCL-2(F104L)-CART19 synergized with venetoclax in multiple lymphoma xenograft models. Furthermore, we uncovered that BCL-2 overexpression in T cells per se enhanced CART anti-tumor activity in preclinical models and in patients by prolonging CART persistence.

With increasing interest in enrolling adolescent patients in adult trials, a question often arises: when can pediatric patients use adult dosages? For currently approved therapeutic monoclonal antibodies (mAbs) with equivalent adult and pediatric indications, body weight thresholds for pediatric patients to receive adult doses vary from 30 to 75 kg. Our objective is to determine if a consistent weight threshold can be recommended for therapeutic mAbs with wide therapeutic windows. Simulations were run to predict exposure using a population pharmacokinetic model describing the typical PK characteristics of a mAb with linear elimination. Simulated steady‐state areas under the concentration‐time curves (AUCss) were compared between pediatric and adult populations. Exponent values of 0.50, 0.75, and 1.0 for the allometric relationship of weight on clearance were also evaluated. Following administration of the same fixed adult dosage in pediatric subjects above a given threshold, median AUCss in the pediatric subjects increased with decreasing weight thresholds. Pediatrics with a minimum weight of 40 kg had median AUCss within 20% to 30% above adult median AUCss when the reference adult population had a median weight ≤80 kg. Higher relative pediatric exposures were seen in lower‐weight pediatric subjects when the weight exponent on clearance was >0.75. Simulations suggested that a weight threshold of 40 kg could generally be considered for pediatric subjects to receive the adult dosage for therapeutic mAbs with linear pharmacokinetics. Weight threshold selection should be based on considerations of therapeutic index of the drug product, weight distribution of the reference adult population, and magnitude of weight effect on pharmacokinetic parameters.

Immunotherapy has revolutionized the treatment of cancer. In particular, immune checkpoint blockade, bispecific antibodies, and adoptive T-cell transfer have yielded unprecedented clinical results in hematological malignancies and solid cancers. While T cell-based immunotherapies have multiple mechanisms of action, their ultimate goal is achieving apoptosis of cancer cells. Unsurprisingly, apoptosis evasion is a key feature of cancer biology. Therefore, enhancing cancer cells’ sensitivity to apoptosis represents a key strategy to improve clinical outcomes in cancer immunotherapy. Indeed, cancer cells are characterized by several intrinsic mechanisms to resist apoptosis, in addition to features to promote apoptosis in T cells and evade therapy. However, apoptosis is double-faced: when it occurs in T cells, it represents a critical mechanism of failure for immunotherapies. This review will summarize the recent efforts to enhance T cell-based immunotherapies by increasing apoptosis susceptibility in cancer cells and discuss the role of apoptosis in modulating the survival of cytotoxic T lymphocytes in the tumor microenvironment and potential strategies to overcome this issue.

Supplementary Figure from Modulation of BCL-2 in Both T Cells and Tumor Cells to Enhance Chimeric Antigen Receptor T-cell Immunotherapy against Cancer

Supplementary Figure from Modulation of BCL-2 in Both T Cells and Tumor Cells to Enhance Chimeric Antigen Receptor T-cell Immunotherapy against Cancer