Improving the therapeutic index in adoptive cell therapy: key factors that impact efficacy

Abstract

The therapeutic index (TI) is a quantitative assessment of a drug safety proportional to its effectiveness. The estimation is intuitive when the engagement of the product with its target is dependent on stable chemistry and predictable pharmacokinetics as is the case for small molecules or antibodies. But for therapeutics with complex biodistribution and context-dependent potency such as adoptive cell therapy (ACT) products, TI estimations need to consider a broader array of factors. These include product-dependent variability such as functional fitness, unpredictable pharmacokinetics due to non-specific trapping, sequestration and extravasation into normal tissues and variable rates of in vivo expansion. In the case of solid malignancies, additional modifiers dependent on individual tumor immune biology may affect pharmacodynamics, including differential trafficking to benign compared with cancer tissue, hampered engagement with target cells, immune suppression and cellular dysfunction due to unfavorable metabolic conditions. Here, we propose a patient-specific assessment of factors affecting on-tumor from off-tumor activity in disparate immunologic environments that impact ACT’s clinical efficacy and may favorably balance the TI. for ACT products.

Advances in Adoptive Cellular Therapy (ACT)

“…It is critical to measure of cellular therapy's effectiveness as variations may occur in various steps, starting from isolation of cells to its re-infusion and homing of effective cells to target the cancer cells (Figure 5). For this purpose, a therapeutic index (TI) has been developed [65].…”

“…Advances in Adoptive Cellular Therapy (ACT) DOI: http://dx.doi.org/10.5772/intechopen.95854 Thus, TI of the ACT largely depends on generic factors (T cell potency and fitness, Dispersion, Dysfunction, combinatorial therapies, comorbidities and microbiome) and TME-specific factors (Antigen availability, tumor, immune response related) [65].…”

Letter to the editor: Checking the pulse of adoptive cell therapy for solid tumors. Thoughts from the abstracts submitted to the 35th Annual Meeting of the Society for the Immunotherapy of Cancer (SITC 2020)

“… 2 We recently summarized the sequence of conditions that gage the therapeutic index for ACT, emphasizing the need to enhance T-cell performance with an integrated approach that covers simultaneously all components of T-cell physiology relevant to their successful deployment. 2 …”

“…While T-cell fitness, the impact of ACT on endogenous immune responses, and the durability of cell therapy activity stand as a prerequisite for all purposes of ACT, selection of optimal tumor-specific antigens, efficient trafficking to neoplastic tissues, and overcoming immune exclusion and/ or suppression are challenges pertaining predominantly to solid malignancies. 2 We recently summarized the sequence of conditions that gage the therapeutic index for ACT, emphasizing the need to enhance T-cell performance with an integrated approach that covers simultaneously all components of T-cell physiology relevant to their successful deployment. 2 To gain insights about the current interest in both academia and industry, we surveyed a snapshot of topical activities and checked the pulse of the field.…”

“…2 We recently summarized the sequence of conditions that gage the therapeutic index for ACT, emphasizing the need to enhance T-cell performance with an integrated approach that covers simultaneously all components of T-cell physiology relevant to their successful deployment. 2 To gain insights about the current interest in both academia and industry, we surveyed a snapshot of topical activities and checked the pulse of the field. We conflated in an image (figure 1) content extracted from 94 abstracts submitted, under the subject "cellular therapies", to the 35th Anniversary Annual Meeting of the Society for the Immunotherapy of Cancer.…”