Bolstered by the success of CTLA4 and PD-(L)1 antibodies, companies are exploring new targets to encourage the immune system to attack tumors.

"While these agents have demonstrated efficacy in a proportion of cancer patients, there clearly is room for improvement to lift the tail of the curve," Michele Teng, associate professor at the QIMR Berghofer Medical Research Institute, told the audience at the clinical trials plenary session of the American Association for Cancer Research Virtual Annual Meeting II, where researchers presented data from a pair of immunotherapies looking to build on the success targeting PD-(L)1.

In an attempt to train the immune system to recognize the tumor, Roche Holding AG has developed RO-7198457, an RNA-lipoplex neoantigen specific immunotherapy. The individualized therapy requires sequencing of blood and tumor samples and prediction of neoantigens specific for the tumor before the drug can be manufactured. Turnaround time for designing and manufacturing the individualized product is currently five to six weeks with good quality samples.

Up to 20 neoantigens are incorporated into two mRNAs – 10 per mRNA construct – which are surrounded by a lipoplex that preferentially delivers the drug to the spleen where it can be taken up by dendritic cells and processed into polypeptide neoantigens that are presented to CD4 and CD8 T cells responsible for killing the tumor.

In a phase Ib dose-escalation study, RO-7198457 in combination with Roche's PD-L1 inhibitor, Tecentriq (atezolizumab), induced T-cell responses within four to six hours after infusion in 73% of 63 patients evaluated. The researchers were able to detect between one and nine neoantigen-specific responses in patients with a median of 2.6 responses per patient.

Unfortunately, the immune response didn't translate into high efficacy, with only one partial response and one complete response observed. "The overall, quite modest, activity in the study is really reflective of both the heterogeneous and heavily pretreated patient population," Juanita Lopez, a consultant medical oncologist at The Royal Marsden Hospital, told the audience while noting that high tumor burden makes it harder for the immune system to have an effect.

Roche has started phase II trials testing RO-7198457 in earlier-stage patients with lower tumor burdens: one testing the drug with Tecentriq as an adjuvant treatment in patients with non-small-cell lung cancer (NSCLC) and a second combining RO-7198457 with Merck & Co. Inc.'s PD-1 antibody, Keytruda (pembrolizumab), as a first-line treatment for patients with melanoma.

PD-1's partner in crime

Basel, Switzerland-based Roche has also developed a more traditional drug, tiragolumab, a monoclonal antibody targeting T-cell immunoreceptor with Ig and ITIM domains (TIGIT), which is expressed on T cells and NK cells.

Tumor cells are able to use TIGIT to inhibit the immune response in multiple ways. The immune cells are directly inhibited by the binding of TIGIT to the poliovirus receptor (PVR) on tumor cells. The PVR-TIGIT interaction also stimulates the tumor to express TGF-beta and IL-10, which modulates antigen presenting cells. Finally TIGIT binds and inhibits CD226, an activator of the immune system.

In the phase Ia portion of the dose-escalation GO30103 study, the monotherapy treatment didn't appear to have much efficacy, but that was expected based on the preclinical mouse models.

"When we designed the trial, we purposely allowed patients to have crossover because we were thinking that there would probably be limited single-agent activity and wanted to give patients on the single agent the opportunity to receive the combination," Johanna Bendell, chief development officer and director of the GI cancer research program at the Sarah Cannon Research Institute, told the audience.

Because TIGIT is often co-expressed with PD-1, the phase Ib dose-escalation portion included Tecentriq, and the combination produced an overall response rate (ORR) of 11% in 44 patients with many of the responders having NSCLC.

In an expansion cohort of patients with PD-L1-positive NSCLC, the ORR for the combination was 46% in 13 evaluable patients, including two complete responses.

Roche has already generated promising preliminary data from the phase II Cityscape trial testing tiragolumab with Tecentriq, which was presented at the virtual American Society of Clinical Oncology (ASCO) meeting and led to Roche launching two phase III trials, Skyscraper-01 and Skyscraper-02.

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