As researchers search for new treat­ments for multiple myeloma, they are particularly interested in uncovering ther­a­pies that address the dis­ease in new ways. Survival and the chance for a cure are likely to be im­proved the most by new treat­ments that are noticeably dif­fer­en­t from other myeloma ther­a­pies.

One of the reasons Darzalex (dara­tu­mu­mab), for example, has been such an im­por­tant new treat­ment for multiple myeloma is because it rep­re­sents a new way of treating the dis­ease. Darzalex was not just another immuno­modu­la­tory agent, like Revlimid (lena­lido­mide) or thalido­mide, and not just another pro­te­a­some in­hib­i­tor, like Velcade (bor­tez­o­mib), Ninlaro (ixazomib), or Kyprolis (car­filz­o­mib). As a mono­clonal anti­body targeted at the CD38 protein found on myeloma cells, Darzalex is the first in an entirely new class of treat­ments for the dis­ease.

This is why tiragolumab, the focus of this edition of the Beacon’s “Getting To Know” series of articles about poten­tial new myeloma ther­a­pies, is so intriguing.

A Monoclonal Antibody Anti-TIGIT Therapy

Tiragolumab cur­rently is being in­ves­ti­gated as a poten­tial treat­ment for multiple myeloma and several other cancers in three dif­fer­en­t clin­i­cal trials. The drug pre­vi­ously has had code names such as RG6058, RO7092284, and MTIG7192A,

Tiragolumab is what is known as an “anti-TIGIT” ther­apy. More specifically, it is a mono­clonal anti­body aimed at a re­cep­tor known as “TIGIT” (rhymes with “digit”), which is found on T-cells and natural killer (NK) cells.

There are no anti-TIGIT ther­a­pies cur­rently approved for the treat­ment of multiple myeloma or, for that matter, any other form of cancer. There are, how­ever, several anti-TIGIT ther­a­pies in the early stages of clin­i­cal trial testing for dif­fer­en­t kinds of cancer, and the anti-TIGIT ap­proach is con­sidered by many researchers to be a promising anti-cancer strat­e­gy.

How Anti-TIGIT Therapies Work

Normally, T cells and NK cells play an im­por­tant role in protecting the body against cancer by attack­ing and helping to kill off cancer cells. The cancer cells that man­age to survive in the body usually do so by finding ways to defend themselves against the immune response mounted by T cells and NK cells.

One way some cancer cells defend themselves against T cells and NK cells is by emitting two types of protein molecules, known as CD112 and CD155, which can attach themselves to the TIGIT re­cep­tors on T cells and NK cells.  When the protein molecules bind to a TIGIT re­cep­tor, it starts a sequence of events that can sig­nif­i­cantly dampen or even shut down the anti-cancer activity of the T cells and NK cells.

Anti-TIGIT ther­a­pies are designed to stop CD112 and CD155 proteins from “putting the brakes” on T cells and NK cells. The ther­a­pies do this by getting to the TIGIT re­cep­tors first, attaching themselves to the re­cep­tors, and preventing CD112 and CD155 from binding to the re­cep­tors.

Importantly, when the anti-TIGIT ther­a­pies attach themselves to the TIGIT re­cep­tors, they do not have the anti-cancer dampening effect that the CD112 and CD155 molecules do.

Anti-TIGIT Therapy Is A Form Of Checkpoint Inhibition

If the way anti-TIGIT ther­a­pies are designed to work sounds familiar, it’s because they belong to a broader group of ther­a­pies known as “checkpoint in­hib­i­tors.” These types of anti-cancer treat­ments work by preventing cancer cells from exploiting immune sys­tem “checkpoints” such as TIGIT to dampen the activity of T cells and NK cells.

Probably the best known checkpoint in­hib­i­tors are ther­a­pies that block cancer cells from targeting a re­cep­tor on T cells and NK cells known as PD-1. Like anti-TIGIT ther­a­pies, PD-1 checkpoint in­hib­i­tors block proteins emitted by cancer cells – in this case, proteins known as PD-L1 and PD-L2 – from binding to the PD-1 re­cep­tor and reducing the anti-tumor response of T cells and NK cells.

PD-1 checkpoint in­hib­i­tors have be­come im­por­tant in the treat­ment of a number of cancers. Myeloma researchers were there­fore op­ti­mis­tic when clin­i­cal trials were started to test whether PD-1 checkpoint in­hib­i­tors such as Keytruda (pem­bro­lizu­mab) or Opdivo (nivolumab) could be used either as single-agents, or together with existing myeloma ther­a­pies, to treat multiple myeloma.

PD-1 Safety Concerns Heighten Interest In Anti-TIGIT Therapies

Unfortunately, safety issues arose in some of the trials testing PD-1-related ther­a­pies in myeloma patients, and many of those trials have been halted. This is one of the reasons, ex­plains Fotis Asimakopoulos, a myeloma specialist at the University of California, San Diego, that researchers are “excited about TIGIT in the case of myeloma." Targeting TIGIT is an alter­na­tive checkpoint-related ap­proach with the poten­tial to im­prove treat­ment out­comes in the dis­ease.

In an interview with The Myeloma Beacon, Dr. Asimakopoulos, who has published a commentary on research related to TIGIT’s role in multiple myeloma, noted that interest in TIGIT as a thera­peutic target is driven by more than just a desire to find a substitute checkpoint in­hib­i­tor for PD-1. “TIGIT,” he ex­plained, “seems to be a major path­way that controls the crosstalk and the rela­tion­ship be­tween immune sys­tem cells [such as T cells and NK cells] and myeloma plasma cells.”

The Phase 1 Trial Of Tiragolumab In Multiple Myeloma

A Phase 1 trial of tiragolumab in multiple myeloma cur­rently is recruiting patients at three locations in the U.S.: Denver, Colorado; St. Louis, Missouri; and Nashville, Tennessee. Additional trial sites are planned for Atlanta, Georgia and Philadelphia, Pennsylvania and four dif­fer­en­t hos­pi­tals in Seoul, Korea.

The Phase 1 trial is recruiting patients with either re­lapsed myeloma or re­lapsed non-Hodgkin lym­phoma. Patients who take part in the first part of the trial will receive treat­ment with just tiragolumab, in­fused once every 21 days. Multiple myeloma patients who start the trial during its second part will receive treat­ment with both tiragolumab and Darzalex.

More in­for­ma­tion about the trial, in­clud­ing eligibility and exclusion criteria, can be found at the trial’s page at clin­i­caltrials.gov.

The Com­panies Developing Tiragolumab

Tiragolumab is being devel­oped by Genentech, a sub­sid­i­ary of the pharma­ceu­tical com­pany Roche. Neither Genentech nor Roche has provided financial or any other form of compensation to The Myeloma Beacon or its employees. To ensure the objectivity of the in­for­ma­tion it provides the myeloma com­munity, The Beacon neither seeks nor accepts financial sup­port from pharma­ceu­tical com­pa­nies or or­ga­ni­za­tions sup­ported by them.

For The Really Curious: Some Additional Odds And Ends

“TIGIT” stands for “T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based in­hib­i­tory motif domains.” “PD-1” stands for “programmed cell death protein - 1.”

Although the discussion in this article mentions both CD112 and CD155 as the molecules that bind to the TIGIT re­cep­tor and dampen T-cell and NK-cell anti-tumor activity, it is believed the CD155 plays the most im­por­tant role.

Anti-TIGIT ther­a­pies may not just stop cancer cells from dampening the anti-tumor activity of T cells and NK cells; they may actually stim­u­late such activity. This is because the protein molecules CD112 and CD155 that dampen immune cell activity by latching on to the TIGIT re­cep­tor also can stim­u­late T cell and NK cell activity if they bind to CD226, a dif­fer­en­t re­cep­tor also found on those immune sys­tem cells.

Thus, anti-TIGIT ther­a­pies, by preventing CD112 and CD155 molecules from binding to TIGIT re­cep­tors, in­crease the likelihood that those molecules end up binding to CD226 re­cep­tors, thereby stim­u­lating the anti-tumor response of the T cell or NK cell.

In short, anti-TIGIT ther­a­pies may do more than release the brake on the immune cells that fight myeloma; they also may step on the gas pedal.