Immunotherapy for Colorectal Cancer

A Review of Current and Novel Therapeutic Approaches

Aaron J. Franke; William Paul Skelton IV; Jason S. Starr; Hiral Parekh; James J. Lee; Michael J. Overman; Carmen Allegra; Thomas J. George


J Natl Cancer Inst. 2019;111(11):1131-1141. 

In This Article

Enhancing Tumor-specific Immunogenicity

Adoptive T-cell Therapies

Another novel treatment option with the potential to augment the host antitumor immune response and enhance the therapeutic efficacy of vaccines is adoptive T-cell therapy. This approach to stimulate tumor immunity involves transfusion of genetically engineered autologous T cells directed at tumor-specific antigens and has demonstrated promising clinical results in a number of hematologic and solid organ malignancies, including a case of metastatic cholangiocarcinoma effectively treated with bioengineered CD4+ T cells.[83] The limitation of this selective, nonmodified adoptive transfer is the restriction to tumor neoepitopes presented by patient-specific MHCs. Recognition of this therapeutic drawback led to the development of T cells genetically designed to express artificial receptors that recognize cancer-specific epitopes independent of MHC presentation, termed CARTs. The use of adoptive T-cell therapy in CRC was first evaluated in a phase I trial in three patients with treatment-refractory mCRC.[84] Patients were transfused with autologous TCRs genetically engineered to express anti-human carcinoembryonic antigen (CEA) epitopes. A response was noted with a substantial decrease in serum CEA levels (74%–99%) and objective tumor regression of liver and lung metastasis in one patient. Of note, all three patients developed severe transient inflammatory colitis.

Expansion of this novel scientific technology was recently demonstrated with the development of "armored" CARTs, allowing modification of T cells to express proteins of potential therapeutic targeting, such as inhibitory ligands that bind PD-1 receptors.[85]

Another noteworthy evolutionary product of the bioengineering era includes bispecific T-cell engagers, which are artificial antibodies composed of a fusion protein containing two individual single-chain variable regions. These two distinct antibody fragments work by simultaneously binding CD3 and tumor-specific surface molecules. Although the therapeutic efficacy of this technology has primarily been evaluated in hematologic malignancies,[86] bispecific T-cell engagers specific to a CRC-associated epitope (CEA) were recently developed, and clinical trial validation is expected.[87]

Despite the success in the treatment of lineage-restricted hematologic malignancies, failure to identity targetable cellular epitopes has limited the utility thus far of chimeric antigen receptor T-cell therapy for solid tumors, although it remains an area of active investigation.[88]

Vaccine-based Therapy

Deficiencies in DNA MMR proteins can cause insertion or deletion mutations, resulting in genomic instability at microsatellite coding sequences and subsequent translation of frameshift peptide antigens. These shared antigens, resulting directly from driver mutations in gene-encoded DNA segments, are considered to be highly immunogenic stimulators of T cells, making them an optimal target for therapeutic vaccines.[89] However, despite this innate biologic opportunity, attempts to establish the role of therapeutic vaccines in CRC through any number of vaccine delivery methods (eg, dendritic cells, autologous tumor cells, recombinant viral vectors, and peptides) have shown mixed results, with limited efficacy in improving clinical outcomes.[90] In an early study of historical interest, 254 patients with surgically resected CRC received adjuvant therapy with active specific immunotherapy (ASI), a vaccine consisting of irradiated autologous tumor cells and Bacillus Calmette-Guérin bacteria.[91] The conclusion from the original investigation was that patients with stage II CRC treated with adjuvant ASI had a recurrence-free survival benefit, which was not observed in patients with stage III disease, initially attributed to differences in tumor burden between the two groups. However, in a recent retrospective analysis, investigators revisited 196 preserved CRC tumor specimens from this study (34/196 dMMR:MSI-H, 17.3%) to assess outcomes relative to MSI status.[92] When compared with surgery alone, patients administered adjuvant vaccine therapy had an improved 15-year recurrence-free survival, irrespective of MSI status and tumor stage (HR = 0.57, 95% CI = 0.34 to 0.94, P = .03). Patients with dMMR:MSI-H CRC were found to have statistically significantly improved rates of 15-year recurrence-free survival compared with pMMR:MSS patients irrespective of treatment arm: 85% vs 64% (HR = 0.45, 95% CI = 0.24% to 0.86%, P = .02). However, the authors failed to find a statistically significant difference in recurrence rates between treatment arms (surgery alone vs ASI) for dMMR:MSI-H patients, suggesting this tumor type has an inherently favorable prognosis.

To evaluate the immunogenic potential of the dMMR genotype, a small phase I–II trial was conducted (NCT01461148) using a peptide vaccine consisting of three frameshift neoantigens commonly associated with dMMR CRC combined with an adjuvant emulsion to promote immunogenicity. The preliminary results of this study reported novel measurable induction of cell-mediated and humoral immunity against at least one frameshift peptide in all 16 vaccinated patients with a favorable toxicity profile.[93] Although no overall clinical outcomes data have been published, preliminary results presented at ASCO 2015 reported stable CEA levels and disease control for more than 7 months after initiating the vaccination protocol in a patient with mCRC.

Further exploration of the interaction between tumor cells and our innate, or "nonspecific," immune system is being investigated through targeting of Toll-like receptors (TLRs), which are cell surface recognition molecules activated by motifs in bacterial DNA, referred to as pathogen-associated molecular patterns. The role of TLR agonists in mCRC is undergoing further testing in multiple early-phase trials, including a TLR3 agonist (poly-ICLC) with pembrolizumab in pMMR:MSS mCRC (NCT02834052), a TLR8 agonist (VTX-2337) in combination with cyclophosphamide (NCT02650635), and a TLR9 agonist (MGN1703) combined with ipilimumab (NCT02668770) and as maintenance following chemotherapy (NCT02077868).

As previously mentioned, identification of tumors with a high CD45RO+ cell (memory T-cell isoform) density is a discriminatory prognostic index associated with improved clinical outcomes and survival.[15,94] Investigators are further evaluating the clinical significance of this marker in a pilot study of an allogeneic CRC vaccine (GVAX) combined with cyclophosphamide and SGI-110, an immunomodulatory agent shown to recruit peritumoral CD45RO+ T-cells.

Although the current evidence for vaccine therapeutics in mCRC represents a mechanistically feasible approach, finding the right antigenic stimulant (or combination thereof) coupled to the right delivery system remains currently elusive.

Immunotherapy for mCRC is rapidly evolving with the potential to revolutionize the treatment of this common disease. As our knowledge of the immune system and its intricacies continues to grow, so will our ability to harness its potential. We have already begun to see the potential of immunotherapy with the breakthrough of anti–PD-1 therapy for the MSI-H:dMMR patient population, such as pembrolizumab and nivolumab. The challenge remains making the therapies effective for all patients, regardless of MSI:MMR status. Efforts are underway to exploit the immune system using traditional and novel therapies, recognizing that one approach may not work consistently for each patient. As highlighted in Table 3, there is an array of promising trials under investigation with the hope to bring these therapies to the clinic.

Alternative attempts to augment host antitumor immune response and enhance the therapeutic efficacy including adoptive T-cell therapies, vaccine-based therapy, TLR agonists, and cell surface recognition molecules activated by motifs in bacterial DNA (ie, pathogen-associated molecular patterns) are each promising areas of active research. Although still in early phases of clinical research, these novel approaches in conjunction with the ongoing pragmatic trials outlined in this article offer many reasons to be optimistic about future immunotherapies for patients with CRC.