Rosenberg Data Cellular Therapy

               11-12-05

Based on NCI results presented at iSBTc meeting 2005

Il-2 (high dose bolus) alone

   Renal 182 CR 7%, PR 9%

   Melanoma 227 CR 9%, PR 10%

   14 year median f/u, CR=cure at the 5% level

   Conclusion: IL-2 activates T cells including T reg cells which reduce T killing.

     T regs are Foxp3+, CD4+ and CD 25+--Anti CD25 (Ontak)

     doesn’t selectively reduce T regs (J ImmRx—28, #6)

IL-7 q-3-wk X 8 increases CD4 & 8 6-7X and does not increase T reg

Anti CTL-4 iv

   Renal 61-ORR-12%, Melanoma 136-ORR-15% 30% of patients get grade III/IV

     autoimmunity(colitis, dermatitis, uveitis, etc.) and this correlated with

     ORR. High dose steroids stops autoimmunity but not antitumor effect.

   This breaks tolerance to produce both effects but activating T cells but doesn’t

   reduce T reg.

Immunization with peptide antigens (melanoma)—600 pts ORR 2.6%--Meta-analysis of

   World literature for cancer vaccines—ORR = 2%--Can increase T cells but no

   ORR

He is doing adjuvant trial of GP100 peptide in Stage resected melanoma—10-30% of

   PBL T cells are antigen specific CD8 but patients still recur—Message- T cells

   alone not enough to break tolerance

TIL cell therapy 10 to 11 th power CLONED CD8 antigen specific (GP100) given to 13

melanoma patients-No ORR—Cells did not persist—gone from PBL in 3 days.

They concluded that host needed to be preconditioned to break tolerance—Gave

Cytoxan 30-60 mg/kg iv x2 + Fludara 25 mg/m sq daily x5 then gave same cloned

cells to 15 patients-- No ORR—Again, cells did not persist in PBL

Asked and received compassionate exemption from FDA for one 16 yo boy who had

failed the above and was soon to die with met mel. Gave him “regular bulk CD4 and 8

TIL—Result—a complete response

35 pts with IL-2 resistant met mel preconditioned by CTX/Fludra chemo treated with

TIL and 51% had ORR, 23% more had responses less than PR. This is LIVING cell

therapy—1 x 10 to 10 th injected which expanded in vivo to6.4 x10 to 10 th by day 7

with 70% of PBL CD8 cells being antigen specific for Mart 1 (JCO 23: 2346)

Now has done >50 pts with > 50% ORR—When it works, works fast—Days to weeks

to ORR even with BULKY disease. PBL morphology full of activated CD8 T cells

with peripheral smear looking like mononucleosis!!!! TIL were heterogeneous and

“body selected” clones that expanded and persisted. Where T cells expanded/persisted in

vivo ORR was 11 of 13 and where cells did not persist only 1 of 13 had ORR.

No specific characteristic for cells that work except for a + correlation with the length of

Telomere.

SO, WHAT IS THE MESSAGE FOR CELLULAR THERAPY THAT WORKS??

Create TIL, activated CD4 and 8 with multiple antigen specificities, grow out the fast

growing cells in vitro with IL-2, precondition pt with chemo or chemo/TBI –infuse cells..

High dose IL-2 probably not essential. Role of IL7, 12, 15 and 21 to be determined in

enhancing ORR. Integration of anti-CTL-4 underway !!

THIS WILL YIELD A RESPONSE RATE MINIMAL/PR/CR OF 75% IN METASTATIC MELANOMA WITH 25-50% OF PATIENTS ALIVE AT 1-2 YEARS   

AND A CURE RATE OF AT LEAST 10-15%. Will surely get better with enhancements

now underway!!!