Non-stem cell transplant cell-based immunotherapy involves isolation of immune cells, in vitro expansion/manipulation to augment anti-tumor immune responses, and transfusion back into the patient (see diagram below). Depending on the context, these cells can either come from the original patient in the case of an autologous transplant, or from a different donor in the case of an allogeneic donor with a matched HLA-type to minimize chances of graft-versus-host disease development in the recipient.

Cell-Based Therapy Scheme

Cell-Based Therapy Scheme

Current clinical use and cell-based immunotherapy research is focused around several immune cell types. This includes the transplantation of anti-tumor T Cells, such as Chimeric Antigen Receptor-carrying T Cells (CAR-T Cells), and cancer antigen-primed antigen presenting cells (APC vaccines). We will discuss these different types of cell-based cancer immunotherapies in the corresponding sections, and future avenues for improving their therapeutic benefit.

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Antigen Presenting Cell (APC) vaccines rely on the ability of APCs to present tumor-specific antigens as foreign to the host immune system, and mobilize an immune response. In this cell-based therapy, APCs (primarily monocytes and dendritic cells) are initially harvested from the peripheral blood of patients. The harvested APCs are then cultured with the following:

 

  • Tumor-specific antigen(s), which is internalized, processed, and displayed by APCs on the cell surface in the form of a MHC-tumor peptide complex.
  • Other soluble factors (such as recombinant proteins) which promote cell maturation and increased immune capabilities.

 

After maturation and “priming” of the APCs ex vivo, they are transfused back into patients where they will elicit anti-tumor immune responses. After activation, they generate effector and memory T Cells to eliminate and surveil tumor recurrence.

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Sipuleucel-T (Provenge®, Valeant) is an FDA-approved APC vaccine used to treat advanced prostate cancer. In this treatment regimen, monocytes are cultured ex vivo with the tumor antigen prostatic acid phosphatase (PAP) linked to recombinant granulocyte-macrophage colony stimulating factor (GM-CSF) to promote maturation into dendritic cells. The patients then receive multiple injections of the cells. Clinical trials showed statistically significant improvement in survival rates amongst castrate-resistant, metastatic prostate cancer patients treated with Provenge® compared to placebo1.


A method to study antigen-specific T cells is the use of MHC tetramers (learn more about tetramer technology in our blog post). BioLegend offers Flex-T™ MHC Monomers and Tetramers, our unique reagents that allow peptide exchange by using ultraviolet light-sensitive peptides. The technology greatly facilitates multicolor tetramer flow. Learn more about our Flex-T™ products.

CAR-T Cells are a variant of genetically-modified T Cells that can be transfused back to patients as a mode of therapy. It is a set of T cells carrying chimeric antigen receptors and a promising therapeutic in adoptive T cell therapy. Unlike traditional T Cells carrying T cell receptors (TCRs) that only recognize foreign antigens bound to MHC molecules, CAR-T Cells carry artificial antigen-recognizing receptors that don’t require an MHC-peptide complex. These receptors are typically introduced into these T cells via transfection of the receptor-coding gene.

CAR composition:

Extracellular Region:
It is typically encoded genetically as a single-chain variable fragment (scFv) which contain a single variable heavy (VH) and light chain (VL) (as opposed to the variable fragment found on normal immunoglobulins, which has 2 sets of VH, VL). Using modern molecular engineering techniques to modify this region, one can generate a vast number of specific chimeric antigen receptors.





Intracellular Region:
Binding of the target antigen to the extracellular component leads to activation of intracellular signaling pathways. Common insertions here are domains taken from the CD3, 4-1BB (CD137), or other co-stimulatory molecules designed to maximize T Cell survival, proliferation, and anti-tumor responses.





KYMRIAH™/Tisagenlecleucel (Novartis) is the first FDA-approved CAR-T Cell based therapy to treat refractory B acute lymphoblastic leukemia (B-ALL). Tisagenlecleucel engineers CAR-T Cells to target the B Cell marker CD19. Clinical trials have shown statistically significant improvement in survival rates in patients treated with Tisagenlecleucel compared to placebo2.

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Educational References
2. FDA’s statement on the Oncologic Drugs Advisory Committee Meeting- Download the PDF

Despite recent advancements in cell-based immunotherapy, there are several obstacles and questions that need to be further investigated and addressed to improve their clinical efficacy in the future. These include, but are not limited to:

 

  • Homing: the anti-tumor cells need to localize to the site of the tumors. How can we properly send the injected immune cells to the tumor site to elicit anti-tumor activity?
  • Tumor microenvironment: the tumors may be in a protected niche, surrounded by anti-inflammatory factors that can dampen anti-tumor immune cell function. How can we modify the cells to overcome this immunomodulation?
  • Intrinsic immune regulatory mechanisms: After generating an immune response, host regulatory mechanisms are in place to dampen inflammation over time. How can we overcome this to prolong anti-tumor immune responses?
  • Target antigen diversity: tumors can express heterogeneous antigen proteins. Can we engineer immune cells to recognize “degenerate” tumor antigens that can overcome this heterogeneity?
  • Foreign vs. Self: tumor cells are altered versions of the host cells, so distinction between a tumor vs. healthy host cell may be difficult. How can we ensure that the immune cells only react and eradicate tumors while keeping healthy host cells intact?

 

Educational References
3. June, C. H. 2017. J Clin Invest. 117: 1466. Pubmed
4. Newick, K. et al. 2017. Ann. Rev. Med. 68:139. Pubmed