Description:
Hematopoietic transplantation and adoptive cellular therapies are expanding fields with increasing established and experimental indications. Even as growing numbers of patients benefit from cell therapy, we are still confronted with addressing two key challenges: that of disease relapse despite these therapies, and that of toxicities that accompany them. This session will present state-of-the-science advances in understanding the basic biology of relapse and toxicity following diverse cell therapies, ranging from allogeneic stem cell transplantation to TCR therapy to chimeric antigen receptor (CAR) T cell therapy. Integrated within the discussions are novel insights gained from the analysis of clinical trials and patient samples, thus providing an opportunity to synthesize biologic features with relevance to confronting these challenges across cellular therapies.

Dr. John F. DiPersio will discuss strategies to enhance efficacy and reduce the toxicity of allogeneic stem cell transplantation (allo-HCT). Allo-HCT remains the best chance of a cure for many patients with newly diagnosed and relapsed hematologic malignancies and marrow failure states. The curative power of allo-HCT rests in the graft vs. tumor/leukemia (GvT/GvL) effect of alloreactive donor T cells. These same donor T cells mediate many of the life-threatening complications of allo-HCT, including graft vs host disease (GvHD), conditioning-associated morbidity, and cytokine release syndrome (in the case of haploidentical stem cell transplantation) limiting success. Furthermore, despite the potential for GvL, a relapse often occurs. The mechanisms of relapse after allo-HCT remain poorly understood, but some patients may be related to defined pathways of immune escape. Dr. Dipersio will discuss pre-clinical mouse models leading to early clinical trials, which explore the use of chemotherapy- and radiation-free conditioning regimens and novel approaches for preventing GvHD. He will also discuss approaches for overcoming immune escape, especially in patients with AML after allo-HCT.  

Dr. Aude Chapuis will discuss novel strategies to improve current anti-cancer treatments employing T cells transduced to express T cell receptors (TCRs). State-of-the-art methods are being used to elucidate challenges to the efficacy of such therapies in individual patients. Based on these newly identified mechanisms, she will discuss how we can now improve the next generation of adoptive T cell therapies. For example, her group has performed intensive gene expression profiling to identify immune evasion mechanisms and the shortcomings of transferred T cells. To overcome these limitations, her group is developing strategies such as multiplexing of high-affinity TCRs, engineering both CD4+ and CD8+ T cells, and tethering a co-stimulatory signal to transferred T cells. In collaborative studies, they use mouse models that recapitulate the human immune environment to validate particular strategies. These results will likely have broad applicability across solid tumors and blood malignancies.

Dr. Chiara Bonini will address the challenges of managing the toxicities associated with genetically engineered T lymphocytes. This revolutionary therapeutic approach is yielding, encouraging signs of efficacy, but these innovative cellular therapy products (TCR and CAR redirected T cells) have shown unique toxicity profiles. Such toxicity may be linked to the target antigen and result from on-target/off-tumor reactions, due to antigen recognition on healthy cells and tissues, such as in the case of B-cell aplasia that follows CD19-CART cell infusion. In other contexts, toxicity may result from cross-reactivity due to the recognition of epitopes structurally similar to the cancer antigen, as observed with TCR-redirected T cells specific for MAGE-A3 or MAGE-A12 peptides. Excessive activation of innate immunity can be triggered by the synchronous activation of infused T cells, resulting in cytokine release syndrome (CRS), in some cases followed by neurotoxicity. Also, the presence of an intact TCR repertoire on engineered T-cells might result in graft-versus-host disease. Several approaches have been implemented to reduce and control toxicity associated with adoptive cellular therapy. Anti-inflammatory compounds such as anti-IL6R or anti-IL6 monoclonal antibodies have proven to be successful in taming CRS. The selection of cancer antigen combined with the proper affinity of the CAR/TCR used might offer new therapeutic windows. Modifications in construct design, the inclusion of suicide genes in transfer vectors, and the implementation of genome-editing tools in cell manufacturing protocols provide unique opportunities to increase the safety profile of adoptive T cell therapy.