Revolutionizing Cancer Immune Cell Therapy: Innovative Approaches to Enhance Targeting, Efficacy and Safety

Immune Cell Therapy Blog – A contribution by Brandon Fletcher, PhD – Medical Affairs, OncoBay Clinical

Immune Cell Therapy Blog Cover Image

Simply put, therapeutic immune cell therapeutics are primarily designed with three main objectives: to enhance/improve (1) target specificity, (2) efficacy, and (3) safety.

The earliest application of leveraging living immune cells as a therapeutic began getting attention in the late 1980’s, when tumor-infiltrating T cells (TILs), isolated from human cancer tumors were used to treat metastatic melanoma NCI, Rosenberg).  Such endeavors fueled the immune cell therapy category ranging from cancer, to infectious disease to autoimmune disease.  Out of the 32 FDA approved cell and gene therapies, the evolution of adoptive cell transfer (ACT) therapeutics from the original TIL work has brought us 6 approved and clinical-medicine altering therapeutics for cancer patients in just the past 5 years, with TIL therapy on the heels of approval.

However, yet we are still working out the kinks, as the challenges were not inconsequential; 1) the isolation/preparation of large numbers of ‘functional’ immune cells (mostly T), native tumor-suppression (evolution within tumors to evade and/or suppress attack, immune cell exhaustion (immune cell loss of function in tumor microenvironment and/or areas of high tumor antigen burden.  So the industry pivoted slightly to broaden our arsenal.

In such, we began exploring the manipulation, basically the genetic engineering of immune cells, which can be performed either ex vivo prior to infusion of the cell therapy or directly in the subject. Genetic engineering has played a critical role in the development of clinically effective cancer immunotherapies, most notably in the broader categories of; engineering of antigen receptors (CARs and TCRs etc.), pathway manipulation (genetic modification of intracellular pathways that modulate natural processes related to tumor survival [proliferation, metabolism, destruction etc.]), and bringing forth genes that provide new functions to immune cells, aka accessory genes.

Currently, the main target cell in such ACTs has been the T cell, for obvious reasons.  However, the immune cell of choice continues to be challenged and we are developing potential therapeutics also using alpha/beta T cells, gamma delta T cells, natural killer (NK) cells, macrophages, marrow infiltrating lymphocytes and dendritic cells, to name just a few, derived in the autologous/patient-derived setting or the allogeneic/“off the shelf” settings.  Or even a step further, the cell may be ‘sourced/created’ through technologies using induced pluripotent stem cells (iPSCs) or entirely engineered cell lines.

Cancer immunotherapy (aka Immune-Oncology, I/O) has taken center-stage in the topic of promising medicinal advancements for cancer patients. There are thousands of I/O clinical trials and hundreds of companies developing all sorts of novel modalities and technologies, or addressing the challenges of the current modalities, however significant barriers remain, notably, those which may not be completely overcome by engineering strategies.  Antigen escape/antigen loss, duration of response due to cell exhaustion, heterogeneity of antigen expression, inefficient tumor infiltration, lack of persistence, and natural or tumor-derived immunosuppression – all continue to be a challenge. Moreover, although we have made strides in the critical-toxicity profile of immune cell therapies, such as CRS and ICANs, they remain a significant concern.  How are we attempting to address these concerns?  Genetic manipulation.

Ongoing efforts in ex vivo and in vivo cell engineering are underway to address each of these challenges. A full depth and breadth of these approaches is beyond the scope of this blog, but a few key examples are below to spark discussion (1).

Antigen Receptor Engineering

The buzzwords ‘Chimeric Antigen Receptor’ are likely spinning in our heads daily, as CARs are the most-studied receptors in ACTs. This receptor is engineered to fine-tune signaling, introduce remote controls, and to implement logic computation circuits (1). CARs incorporate both TCR and costimulatory receptor signaling domains that control T-cell proliferation, effector function, and metabolic fitness. An advantage of CARs over TCRs is their ability to target any surface antigen independent of patients’ MHC haplotype, but with the consequence of also having a lower antigen sensitivity.

TCRs are well known for their ability to target intracellular antigens, unlike standard CARs.  To address such differences, new hybrid receptor designs have emerged, such as TruCs (T cell Receptor fusion Constructs), which link antibody domains to different components of the TCR complex, STARs (Synthetic TCR and Antigen Receptors) and HITs (HLA-Independent TCRs) -which are both synthetic receptors fusing antibody binding domains to the native TCR receptor constant regions, and lastly, the multi-antigen approach of OR-gate CARs-which address antigen escape (1).

Ex vivo cell engineering

Engineered immune cells capable of sensing and ‘intelligently’ responding to various stimuli with measured efficacy continue to be developed. Here, the clinical cell design objectives are typically achieved through three genetic and molecular engineering approaches, such as: (i) receptor engineering, (ii) host cell genome engineering, and (iii) therapeutic payload co-engineering – all three warranting significant further safety and efficacy exploration (1).

Therapeutic payload co-engineering

Engineering immune cells to express therapeutic payloads provides an additional opportunity for modulating cell function. When combined with CAR expression, they are sometimes referred to as “armored” CARs or TRUCKs (T-cells Redirected towards Universal Cytokine Killing).

Genome Engineering

Involves the engineering of the immune cell genome to enhance the safety and efficacy profile in cell therapy. Currently, such endeavors utilize engineered viruses, which randomly integrate payload DNA into the genome of donor cells, presenting the possibility of causing unregulated cell growth and cancer. Targeted integration at defined genomic locations, genome editing enzymes such as CRISPR/Cas is evolving to leverage electroporation with in efforts to remove the err that the genome editing enzyme will persist.

Immune cell manufacturing:

We are all well aware of the challenges in ACT manufacturing, which has certainly impacted their ease and potential. Logistics is the crux of these challenges, involving deep complexities in managing chain-of-custody and chain-of-identity of all the ‘living’ materials. Furthermore is the concern over utilizing viral transduction to deliver DNA payloads, which has a high failure rate. Hence, we are seeing an expansion of non-viral approaches to gene delivery, and  significant resources have been devoted to developing allogeneic/“off-the-shelf” cell therapeutics.

In vivo cell engineering

These technologies include materials used to place transferred immune cells at the desired site, targeting of transferred cells via externally controlled cues, and direct genetic manipulation in the organism/human.

This is such an exciting time for cancer discovery and promise for patients.  We at OncoBay are focused on immune-oncology therapies, with the lead focus on cell therapeutics. 85% of our staff are deeply experienced in cell therapy, and we average over 15 years’ experience in the field, yet, even we continue to be in awe of the accelerated pace to meaningful outcomes in the cell therapy space.  The opportunities, angles, strategies and novel modalities appear to be endless.  Is there room for predictive computational modeling and AI-based data analysis here? What about the correlative application of larger systems  to better describe the interactions of cell therapies with the endogenous immune system, the nervous system?  Lastly, what might be the role of the gut microbiome in neo-oncogenesis and tumor proliferation and survival?  We would love to hear your thoughts.



  1. Irvine DJ, Maus MV, Mooney DJ, Wong WW. The future of engineered immune cell therapies. Science. 2022 Nov 25;378(6622):853-858. doi: 10.1126/science.abq6990. Epub 2022 Nov 24. PMID: 36423279; PMCID: PMC9919886.

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