TCR T cells towards solid tumors: perspective on pitfalls and opportunities

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TCR T cells towards solid tumors: perspective on pitfalls and opportunities

TCR T cells towards solid tumors: perspective on pitfalls and opportunities

Reno Debets, founder and CSO, PCT BV, Rotterdam, the Netherlands



Adoptive T cell therapy refers to the infusion of tumor-reactive T cells that recognize and kill malignant cells. Adoptive T cell therapy is built on the principle of isolation of T cells from a patient, T cell expansion and activation ex vivo, and re-infusion of these T cells back into the patient. This therapy, when using T cells with introduced genes encoding T cell receptors (TCRs), has already resulted in impressive clinical responses in a number of human malignancies, such as metastatic melanoma, synovial sarcoma and multiple myeloma. Besides clear objective responses (OR: 55-80%), these studies demonstrated durable complete regressions (CR: 2-20%).


Current pitfalls

  • Accessibility and safety are hampered due to lack of tumor-specific targets to treat large cohorts of patients with solid tumors

The ability of TCRs to effectively and safely target tumors is primarily governed by the presence of target antigens in a tumor type, its absence in normal, healthy tissue, and its restriction by HLA alleles. In example, TCRs targeting the melanoma targets MART-1 or gp100 have led to severe toxicities caused by lack of absence of these targets outside tumor tissues (so-called on-target toxicity). In another example, in metastatic melanoma, NY-ESO1, with no evidence for on-target toxicity, is expressed in about 25% of patients (by at least 5% of tumor cells). In case TCRs target NY-ESO1 in the context of HLA-A2, then (with about 45% frequency of HLA-A2 in the Caucasian population) the targetable cohort size scales down to only 11%.


  • Longevity of tumor-specific T cells is limited due to affinity-enhancement of TCRs

The ability of TCRs to effectively and safely target tumors is, besides their targets, also governed by the specificity and sensitivity of the therapeutic TCR itself. Notably, affinity-enhancement of TCRs, although generally enhancing the sensitivity, corrupts the specificity of T cell responses. In example, TCRs targeting MAGE-A3 led to severe toxicities caused by recognition of targets highly similar to MAGE-A3 outside tumor tissues (so-called off-target toxicity). Moreover, affinity-enhancement of TCRs poses the additional (and often unrecognized) risk that T cells show signs of early differentiation and become functionally exhausted by negative regulators, such as the surface expression of the immune checkpoint PD1 (own laboratory data); thereby preventing long-term T cell persistence and anti-tumor responses.



  • Response in solid tumors is limited due to the suppressive immune micromilieu

Multiple clinical trials demonstrated variable therapeutic efficacy, which in case of solid tumors has been largely attributed to the suppressive nature of the tumor micro-environment (TME). Indeed, no or negligible responses following adoptive T cell therapy are often accompanied with no or low T cell influx, antigen recognition and/or function of intra-tumoral T cells. In example, NY-ESO1 TCR T cells did not demonstrate objective responses in about half of the patients with metastatic melanoma, and MAGE-A4 TCR T cells did not demonstrate an objective response in any of the patients with esophageal carcinoma. The observed no-response is not due to loss of target antigen, but most likely to deficits in the number and function of T cells that arrive in the targeted tumor.


In short:

  • there is a clear lack of tumor-specific and safe targets, particularly those that cover multiple tumors and are expressed at high-levels in substantial fractions of patients.
  • gene-enhancement of TCRs demonstrates risks towards safety and efficacy of T cell responses.
  • certain tumor subtypes are refractory to T cell treatment in case not providing co-treatments/strategies to enhance numbers and/or function of intra-tumoral T cells.


Current opportunities

  • Targets: tapping into a new pool of intracellular, pan-cancer-specific antigens

Target antigens should ideally fulfill the following criteria: (i) ability to elicit a CD8 T cell response; (ii) high and homogeneous expression in multiple types of tumors but not in healthy tissues; and (iii) preferably shared by many patients. Among various target antigens, one can broadly distinguish between targets that are shared versus those that are non-shared among patients. Shared targets, such as those that are over-expressed, as well as differentiation antigens, are unfortunately also expressed in healthy tissues. Non-shared targets, such as neo-antigens, are highly tumor-specific, but often not validated as naturally occurring antigens nor can they be targeted in multiple patients. Importantly, research at the laboratory of Tumor Immunology, department of Medical Oncology, Erasmus MC, has identified 30 intracellular antigens that are highly tumor-specific, present in multiple tumor types, shared among patients and have no precedent in TCR T cell therapy. Early clinical trials with TCRs targeting the tumor antigen NY-ESO-1 and more recently MAGE-A4 ( NCT 04044768), also intracellular antigens, have been successful without treatment toxicities. Notably, the 30 novel targets (other than NY-ESO1 or MAGE-A4; and being part of Pan Cancer T (PCT)’s portfolio) show high-level expressions in multiple types of tumors in high fractions of patients.


  • TCRs: selecting for high-specificity without manipulating the natural affinity

TCRs should ideally be selected according to following criteria: (i) high-specificity; (ii) sensitivity; and (iii) longevity of tumor-specific T cells. With these end-points in mind, one can carefully apply the necessary computational and laboratory techniques to retrieve immunogenic and non-cross-reactive epitopes from the target of interest as well as safe and effective TCRs directed against these epitopes (these techniques are optimized and part of the PCT Target and TCR platforms). The resulting TCRs harbor so-called recognition motifs that do not enable recognition of epitopes other than the cognate epitope. Also, these non-enhanced TCRs show a sensitivity comparable to NY-ESO1 TCRs that have been clinically tested, and importantly do not result in early up-regulated expression of negative regulators, such as PD1.


  • TME: immune profiling to select drugs and/or genetic strategies to antagonize suppression

Solid tumors are heterogeneous with respect to number, location and activation state of intra-tumoral CD8 T cells. Of interest, local T cell immunity provides significant predictive value for adoptive T cell therapy that goes beyond markers of mere tumor mutational load. Parameters capturing local T cell immunity include: influx of T cells; antigen recognition by T cells; and/or function of T cells. These three categories are defined by unique immune markers, and recent advances in in silico and microscopy tools have enabled accurate charting of the immune profile of tumors (these techniques are part of PCT’s 3rd platform: the TME platform). The resulting immune profiles in turn guide rational selections for co-treatments (i.e., immune-modulating drugs) or genetic strategies. The latter strategies entail additional gene engineering of T cells to provide controlled resistance to local suppression (only those T cells seeing the target inside the tumor), a rationale previously designed and tested by our laboratory.


In short (listing the opportunities of PCT’s platforms):

  • distinct expression profiles of PCT targets that enable the targeting of size-able HLA-A2+ patient cohorts, and warrant the exploitation of TCRs restricted by non-HLA-A2 alleles.
  • non-modified TCRs that are not cross-reactive against non-cognate epitopes, and preserve natural T cell persistence and responses that are not curtailed by early T cell exhaustion.
  • Accurate immune profiles of hard-to-treat solid tumors that enable the identification of dominant T cell-evasive pathways, and down-stream selections of drugs or engineering strategies to co-treat T cell-refractory tumors.


Other challenges and solutions regarding adoptive T cell therapies

Development and clinical implementation of adoptive T cell therapies heavily (if not completely) rely on centers of expertise, with specialized MLII/DMII laboratories, facilities to produce Advanced Therapeutic Medicinal Products (ATMPs, in this case, TCR T cells) as well as highly-trained researchers, manufacturing specialists, pharmacists and clinical oncologists. Due to the current complexity of the manufacturing of ATMPs, quality-controls, and clinical protocols, adoptive cellular therapy is challenged by high costs and relatively long vein-to-vein times.


Early successes with CAR T cells in the treatment of hematological malignancies have paved the way for fast technological developments in the field of gene-engineering of T cells, such as gene-editing (i.e., knocking-out endogenous TCR loci). Although gene-editing of T cells is not yet mature, it is expected that this development leads to safe TCR T cells, and potentially sets the stage to the therapeutic use of allogeneic rather than autologous T cells. In a more general sense, the fast rate of technological improvements and the existence and broadening of a highly competitive market will likely accelerate the development of cheaper treatments and faster vein-to-vein times.


Notwithstanding the importance of these forward-moving developments, the current focus should be on the selection of optimal targets, TCRs and TME-sensitizing co-treatments. In line with this perception, and to keep momentum, first clinical trials should be based on established protocols for manufacturing and patient treatment (such as the one of the Erasmus MC MAGE-C2 TCR T cell trial) and subsequent trials should integrate significant technological developments. It is exactly this principle, PCT is adhering to.