Table 5 Challenges, opportunities, and future directions

HLA Subtype Compatibility (HLA-A*02:01)

Therapies inclusive only to HLA-A*02:01 positive patients. Serotype is highly prevalent in Caucasian and native American populations yet low in other races and ethnicities

Broadening these therapies to multiple HLA genotypes and subtypes will increase the inclusivity and availability to a wider range of patients

Histological Biomarker Analyses

Costly and invasive tumor biopsy step needed to screen tumor tissue for confirmed expression of the targeted antigen

Develop new techniques to transcend current biopsy logistics and costs. Consider emerging circulating tumor cell techniques to identify target antigens

Identification and Selection of Target Antigens

Translational retroactive studies focusing on correlating data to identify suitable tumor antigens that are unique to a specific cancer and activate the immune response

Utilize bioinformatics technologies to develop predictive algorithms to identify effective target patient populations and tractable tumor antigens that enhance on-target, on-tumor immunocompetent responses and attenuate on-target off-tumor untoward effects

Leukapheresis Techniques and Manufacturing Starting Material

Current process is to extract and isolate PBMCs via standard apheresis techniques and utilized as the initial material for genetic modification

Advance apheresis techniques and improve autologous procedure technologies by enriching and activating T-cell subpopulations as the starting material

Temporal window from leukapheresis to product delivery

Current median times from leukapheresis to product delivery is 2–3 weeks

Augment and enhance the manufacturing, development, and delivery logistics processes to reduce the autologous extraction-to-infusion time frame

Pre-Infusion Lymphodepletion

Standard conditioning method supporting enhancement of engraftment and persistence of modified transferred T-cells

Fine tune and adapt the use of lymphodepletion agents to maximize immunocompetence and clinical benefit

Centralized Manufacturing/Processing Center

Present manufacturing methodology centralizes the preparation of TCR-based adoptive therapy at a core center to be subsequently returned and administered to the patient

Project to create regional or hospital-based centers where the extraction, modification, and infusion of the T-cell product occurs at the same location

Protracted Patient Follow-Up

Current regulatory guidance recommends patient follow-up for 15 years to screen for untoward long-term effects

Innovate post-administration safety assessments to efficiently monitor patients as well pioneering pre-infusion translational research studies that demonstrate the safety longevity of genetically-modified cells

Screening for optimal TCR affinity

Naturally occurring, tumor‐reactive T-cells might have poor efficacy because of the expression of low‐affinity TCRs

High affinity T-cells specific for candidate tumor antigens that are non-mutated self-antigens are likely candidates for such negative selection. Various strategies have been developed to enhance the affinity and the functional avidity of TCRs targeting tumor antigens. However, affinity‐enhanced TCRs might increase the risk of autoimmunity [150, 151]

Combination with checkpoint blockade

Immune checkpoint inhibitors, such as PD-1/PD-L1 and CTLA-4 along with other treatment modalities have been widely considered in the engineered TCR clinical trials

Approaches interfere with these inhibitory receptors are being tested to further enhance the antitumor activity of engineered T-cells [152,153,154,155]. Checkpoint inhibition could, if administered before T-cell harvest, may facilitate the T-cells to be used for ACT product manufacture. This type of treatment could potentially be used to improve the quality of ex vivo expanded T-cell immunotherapy [156]. However, increasing upregulated expression of inhibitory receptors may limit the anti-tumor response by T-cell exhaustion

TCR-edited T-cells

The CRISPR-engineered T-cells may facilitate recognition of tumor cells by deleting the endogenous TCRs and PD-1 to reduce T-cell exhaustion

CRISPR-Cas9 technology was used in an example as a synthetic, cancer specific TCR transgene (NY-ESO-1) to facilitate recognition of tumor cells by the engineered T-cells. T-cells expressing NY-ESO-1 and lacking PD-1 and endogenous TCR have sustained in vivo expansion and persistence in a pilot phase I trial, suggesting additional tumor antigens may be required to see full tumor response [157]