Immunotherapy of Advanced Colorectal Cancer By Enlisting Bystander T Cells

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Mario Sznol, MD
Mario Sznol, MD

The immune checkpoint inhibitors, which include antagonist antibodies against PD-1, PD-L1, or CTLA-4, demonstrate activity against a broad range of tumors, but produce only minimal activity in advanced colorectal cancer (CRC), except for the subset with high mutation rates from DNA mismatch repair deficiency.

One of the proposed reasons for resistance is the low frequency of tumor antigen-specific T cells within the microenvironment of colorectal cancer metastases. T cells with specificities for non-tumor antigens can be found within the microenvironment of tumors; these T cells are either resident within the tissues or are simply entering and exiting the tumor over time.

One potential approach to induce immune-mediated anti-tumor effect is to redirect non-specific T cells to kill or secrete cytokines when in close proximity to tumor cells. At the 2017 American Society of Clinical Oncology (ASCO) meeting, investigators led by Dr Josep Tabernero presented the results of a phase 1 dose escalation trial (ClinicalTrials.gov Identifier: NCT02324257) of a bispecific antibody recognizing carcinoembryonic antigen (CEA) and CD3 (CEA-TCB).1

The bispecific antibody crosslinks CEA-expressing tumor cells to CD3 on T cells, which activates the T cells, resulting in both cytokine production and release of cytotoxic proteins and consequent tumor cell death.

Because T cell activation upregulates expression of the inhibitory receptor PD-1 and its ligand PD-L1 on surrounding tumor and immune cells, a companion dose escalation trial (ClinicalTrials.gov Identifier: NCT02650713) was conducted combining the CEA-TCB bispecific with the anti-PD-L1 antibody, atezolizumab.

As a monotherapy, CEA-TCB was administered intravenously weekly. The most common adverse events were fever, infusion-related reactions, and diarrhea. Tumor regression was observed in several patients, including partial responses in 2/31 metastatic patients with CRC receiving doses from 60 to 600 mg weekly.

A similar spectrum of adverse events was observed with the combination of CEA-TCB administered intravenously weekly and atezolizumab 1200 mg IV every 3 weeks. In the combination, CEA-TCB doses of 5 to 160 mg were administered, and a maximum tolerated dose (MTD) had not been reached, although 600 mg exceeded the MTD as a monotherapy.

Most significantly, among the 11 heavily pre-treated metastatic patients treated at the 80 or 160 mg dose with atezolizumab, 8 demonstrated tumor regression including 2 partial responses. Although the phase 1 combination trial is not complete and follow-up is short, the results point to a major advance for immune therapy in advanced CEA-expressing CRC and possibly other CEA-expressing malignancies.

Reference

  1. Tabernero J, Melero I, Ros W, et al. hase Ia and Ib studies of the novel carcinoembryonic antigen (CEA) T-cell bispecific (CEA CD3 TCB) antibody as a single agent and in combination with atezolizumab: Preliminary efficacy and safety in patients with metastatic colorectal cancer (mCRC). J Clin Oncol. 2017;35(suppl; abstr 3002).

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