Results from phase Ia and phase Ib studies on the preliminary therapeutic activity and safety of the novel carcinoembryonic antigen (CEA) T-cell bispecific (CEA CD3 TCB ) antibody, either as monotherapy or in combination with PD-L1 inhibitor atezolizumab, were presented during an Oral Abstract Session on Developmental Therapeutics - Immunotherapy by Josep Tabernero, Director of VHIO, and Head of the Medical Oncology Department of the Vall d´Hebron University Hospital (HUVH).

Study authors, also including Guillem Argilés, Medical Oncologist and physician-scientist of VHIO´s Gastrointestinal and Endocrine Tumors Group led by Josep Tabernero, explored the preliminary tolerability, safety and potency of this new immunotherapeutic, administered ´solo´ or twinned with atezolizumab, in patients with metastatic colorectal cancer (mCRC) whose tumours expressed the CEA protein.

In both studies, presented jointly, this experimental antibody, RO6958688, succeeded in checking the favourable side effect profile and empowered efficacy boxes - even in tumours that traditionally resist current immunotherapies.

Acting as binding node to facilitate interaction between anti-tumour T lymphocytes and tumour cells expressing the CEA protein, RO6958688 is designed to attach to CEA as well as connect to the T lymphocyte receptor.

In so doing, this approach promotes the activation of immune cells to recognise, attack and destroy tumour cells.

Under normal circumstances T lymphocytes can detect and destruct cancer cells but in advanced disease this capacity is inhibited through a myriad of mechanisms.

This novel agent can restore this function and rescue the anticancer immune response in certain patients with CEA-positive tumours.

Considering that CEA is expressed in 95% of colon cancers, this approach could therefore provide a promising future avenue towards better treating this tumour type - currently ranking second in incidence and occupying the number two spot in leading causes of death from cancer in Spain.

To-date only 5% of these tumours respond to the current suite of anti-cancer immunotherapeutics.

Further, since these patients no longer respond to standard therapies, the need to identify new and more effective ways of treating their cancer is critical.

Both in experimental models and these early phase clinical trials CEA-TCB, the first T-cell bispecific antibody with a novel 2-to-1 format, has as monotherapy shown promising anti-cancer activity in heavily pre-treated patients with mCRC.

Results also showed enhanced clinical benefit when administered in combination with the PD-L1 inhibitor atezolizumab.

“Advanced colorectal cancer poses a major challenge for oncologists since this tumour type notoriously develops resistance to current therapies. Driving faster, more effective treatments ‘in mono’ or as drug-drug combinations is paramount if we are to ultimately succeed in reversing cancer drug resistance and thus improve outcomes for these patients”, observes Josep Tabernero, first author of the two studies.

The two trials also established therapeutic dose and favourable side effect and safety profiles both as monotherapy and in combination with atezolizumab.

Importantly, the side effects observed, including cancer pain, fever, chills, fatigue and diarrhoea, both matched those anticipated and could be successfully managed and treated, and no unforeseen toxic effects were reported.

While these preliminary data are undoubtedly encouraging, it is still very early days.

Since this research was conducted in small clinical trials these findings must be corroborated in larger studies before this pioneering approach can be fully considered as a realistic, proven therapeutic option for patients with cancers expressing CEA.

Importantly, while the administration of the RO6958688 bispecific antibody either alone or paired with atezolizumab showed promise, its effect was more potent in combination.

Ongoing and future studies will therefore continue to further explore this combinatorial approach.

“When this bispecific antibody is administered as monotherapy we see an initial response but, at the same time, it starts to express PD-1/PD-L1 to render the immune system dormant which leads to disease progression.

When the agent is delivered in combination with the PD-1/PD-L1 inhibitor, there is rating of 82% in response and stabilisation of disease”, explains Tabernero.

“We are seeing compelling evidence on the use of novel immune agents as mono therapy or in combination across an increasing number of malignancies. Our results presented today at ASCO show promise in boosting the immune system to mount an effective antitumour response against metastatic colorectal cancer”, he concludes.

Source: VHIO