Can­cer-killing virus acts by alert­ing im­mune sys­tem

Iran Daily - - Health -

un­der­ly­ing mech­a­nisms of these vi­ral ther­a­pies, a col­lab­o­ra­tion was forged be­tween UCSF vas­cu­lar re­searcher Don­ald Mcdon­ald, MD, PHD, and re­searchers at San Fran­cisco-based biotech Sil­la­jen Bio­ther­a­peu­tics Inc. (for­merly Jen­nerex Bio­ther­a­peu­tics, Inc.), a sub­sidiary of Sil­la­jen, Inc., head­quar­tered in South Korea.

Sil­la­jen is de­vel­op­ing an on­colytic vi­ral ther­apy called Pexa-vec, cur­rently in phase III and phase IB-II clin­i­cal tri­als for use against pri­mary liver and col­orec­tal can­cers, re­spec­tively.

Pexa-vec is an en­gi­neered virus based on the harm­less vac­cinia cow­pox virus — also the ba­sis for the orig­i­nal small­pox vac­cine.

Early ob­ser­va­tions sug­gest­ing that the virus might at­tack can­cer in part by dam­ag­ing blood ves­sels that feed tu­mor growth led the Sil­la­jen team to strike up a col­lab­o­ra­tion with Mcdon­ald, an ex­pert in tu­mor vas­cu­la­ture, to in­ves­ti­gate the virus’s mech­a­nism of ac­tion in an­i­mal mod­els.

Mcdon­ald, a mem­ber of the UCSF He­len Diller Fam­ily Com­pre­hen­sive Can­cer Cen­ter and the Car­dio­vas­cu­lar Re­search In­sti­tute at UCSF, said, “This got my at­ten­tion in part be­cause this virus could be given sys­tem­i­cally by in­tra­venous in­jec­tion, in con­trast to most on­colytic viruses that are in­jected into the tu­mor it­self, which ob­vi­ously lim­its their ther­a­peu­tic po­ten­tial against can­cers that are in­ac­ces­si­ble or have spread to mul­ti­ple sites in the body.”

The Pexa-vec virus was orig­i­nally de­vel­oped by Michael Mas­trangelo, MD, and Ed­mund Lat­time, PHD, of Thomas Jef­fer­son Uni­ver­sity in Philadel­phia, who en­gi­neered the harm­less vac­cinia virus to in­fect only can­cer cells and other rapidly di­vid­ing cells, as well as to stim­u­late im­mune ac­tiv­ity, in hopes of boost­ing the im­mune re­sponse to tu­mors.

To study how the mod­i­fied virus at­tacks tu­mors, re­searchers in the Mcdon­ald lab in­jected it in­tra­venously into mice ge­net­i­cally mod­i­fied to de­velop neu­roen­docrine pan­cre­atic can­cer.

They found that the virus failed to in­fect healthy or­gans or make the an­i­mals ill, but suc­ceeded in in­fect­ing blood ves­sels within tu­mors. These ini­tial in­fec­tions caused the ves­sels to leak and ex­pose the tu­mor cells to the virus.

In these ex­per­i­ments, the virus man­aged to in­fect and de­stroy only a small pro­por­tion of tu­mor cells di­rectly, the re­searchers found, but within five days of the ini­tial in­fec­tion, the rest of the tu­mor be­gan to be killed by a pow­er­ful im­mune re­ac­tion.

Mcdon­ald said, “At first small spots of the tu­mor were in­fected, but then most of the tu­mor started to die.

“We were able to show that while only about five per­cent of cells were in­fected by the virus, the num­ber of cells that were killed was more than ten times higher. As far as I know, no one has ever done this kind of anal­y­sis.”

The re­searchers found that by killing some tu­mor cells di­rectly, the vi­ral in­fec­tion ex­posed tu­mor pro­teins that could be de­tected by the im­mune sys­tem, trig­ger­ing an im­mune at­tack on the rest of the tu­mor.

The re­searchers demon­strated this by tem­po­rar­ily get­ting rid of the im­mune sys­tem’s can­cer-killing cells, called CD8+ or cy­to­toxic T cells, and show­ing that with­out these cells, the virus killed only the ini­tial five per­cent of can­cer cells.

Mcdon­ald’s team won­dered whether they could im­prove the ef­fi­cacy of the virus by adding in a se­cond drug called Su­tent (suni­tinib) that blocks blood vessel growth and al­ters im­mune func­tion.

The com­bi­na­tion worked, with sig­nif­i­cantly greater tu­mor killing than with the virus alone.

When the re­searchers ex­am­ined the tu­mors, they dis­cov­ered that the se­cond drug acted by mak­ing the im­mune sys­tem hy­per-alert to tu­mor pro­teins re­leased by the vi­ral in­fec­tion, rather than through ef­fects on tu­mor blood ves­sels

This find­ing sug­gests that pair­ing Pexa-vec’s abil­ity to awaken the im­mune sys­tem to pre­vi­ously ig­nored signs of can­cer with the new­est gen­er­a­tion of check­point in­hibitors, which act by un­leash­ing the im­mune sys­tem’s full force, might be an ex­tremely po­tent com­bi­na­tion ther­apy.

Mcdon­ald said, “The ques­tion with im­munother­apy has al­ways been—why doesn’t the im­mune sys­tem nat­u­rally de­tect and at­tack can­cer cells?”

“It seems like these viruses are like set­ting off a bomb that jars the im­mune sys­tem. The in­fec­tion re­leases tu­mor anti­gens in a way that jump-starts the im­mune re­sponse.”

In an ef­fort to fur­ther ex­ploit the po­ten­tial of Pexa-vec to ac­ti­vate the im­mune sys­tem to fight can­cer, as seen in Mcdon­ald’s pre­clin­i­cal data, Sil­la­jen re­cently an­nounced a new clin­i­cal trial in col­lab­o­ra­tion with New York-based Re­gen­eron Inc. to test Pexa-vec and REGN2810, a PD-1 check­point in­hibitor, in com­bi­na­tion against re­nal cell car­ci­noma, and re­cently signed a spon­sored re­search agree­ment with UCSF to en­able joint sup­port of par­al­lel pre­clin­i­cal ex­per­i­ments by Mcdon­ald’s team.

James Burke, CMO of Sil­la­jen Bio­ther­a­peu­tics, said, “The pre­clin­i­cal work be­ing done by the Mcdon­ald lab has been ex­tremely in­for­ma­tive in help­ing us un­der­stand that Pexa-vec is work­ing like a vac­cine to sen­si­tize the im­mune sys­tem to at­tack can­cer.

“Our on­go­ing col­lab­o­ra­tion will help us un­der­stand how best to com­bine Pexa-vec with im­mune-mod­u­la­tion such as anti-pd1 an­ti­body ther­apy to max­i­mize anti-tu­mor im­mune re­sponse.

“If the virus is ig­nit­ing a fire within the tu­mor, we want to see if we can use these im­mune mod­u­la­tors to pour gas on the flames.”

med­i­calx­ A tu­mor with green patches of vac­cinia virus in­fec­tion sur­rounded by red blood ves­sels.

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