ALBERT

Description: Background: Prevention or treatment of relapsed lymphoid malignancies after SCT requires novel strategies. We previously reported on safety and early responses of ipilimumab combined with lenalidomide in 16 treated patients (pts.) (Khouri et al. Clin Cancer Res, 2018). Here, we update the published data on a larger cohort of pts. with a longer follow-up. In addition, we define immune phenotpyes that correlated with response. Patients andMethods: Pts. with lymphoma or CLL who relapsed after alloSCT, with no active GVHD were eligible. Pts. with autologous SCT were included within 6 mos post-SCT if they were still in CR, but had high risk features for relapse. Treatment consisted of 4 total cycles of lenalidomide 10 mg PO daily for 21 days (cycles 1 and 3) alternating with ipilimumab 3 mg/kg IV on day 1 (Cycles 2 and 4). Considering the favorable safety profile in the initial patients treated, number of cycles was amended to 8 cycles in 6/2017. PBMC's from 20 pts (12 responders and 8 non-responders) were analyzed by flow cytometry. Results: Twenty-two pts. were enrolled. Autologous group (n=11): Median age was 57 yrs (range, 33-68). Histologies included diffuse-large-B-cell lymphoma (DLBCL) [n=6; including 3 with double-hit lymphoma (DHL)], mantle cell lymphoma (MCL) (n=2; one with CNS involvement), Hodgkin's disease (n=2; with persistent PET+ post-SCT), and follicular lymphoma (n=1, PIF with response to 4th line of therapy). Median time to enrollment after SCT was 3.8 months (range, 1.4-5.5). With a median follow-up duration of 23.4 months (range, 10.1- 48), median OS was not reached. Three pts. relapsed at a median of 6.7 months; 1 pt. died after developing T-cell lymph proliferative disorder 2 years after finishing treatment and ten pts. remain alive. The most common other AEs were 19 events of neutropenia (n=5, gr 4; n=2 gr 3, n=12 gr 2), two patients had thrombocytopenia gr 2, and one developed pulmonary embolism. All AEs resolved. An immune-related AE occurred in one patient (dermatitis, gr 3) after the second ipilimumab dose and resolved with steroids. AEs were similar in pts. who received 4 or 8 cycles (n=5). Allogeneic group(n=11): Median age was 55 yrs (range, 44- 66). Histologies included [Follicular (n=2), CLL (n=3), MCL (n=2), DLBCL (n=3; 2 of whom were DHL), and T-cell anaplastic lymphoma (n=1)]. Median number of therapies excluding the alloSCT was 3 (range 2-7). Two failed a prior autoSCT, one had 2 prior alloSCT, and three failed prior donor lymphocyte infusions, and one CLL pt. failed prior FCR, lenalidomide/ofatumumab, ibrutinib, idelalisib, CAR-T cell and venetoclax. Two pts. relapsed within 3 mos of their alloSCT prior to enrollment on study. One pt. was taken off study after cycle 1 of lenalidomide due to flare of previously diagnosed liver and skin GVHD, which responded to steroids. Another pt. developed chronic GVHD after cycle 4 which precluded treatment with the pre-planned 8 cycles. No other cases of GVHD were noted. ORR rate was 73%. Five (45%) pts. had CRs (four of which were durable at 14+, 32+, 33+ and 34+ months; including the CLL pt. who failed small molecule inhibitors and CAR-T), and 3 (27%) had PR. With a median follow-up time of 30.8 mos (range, 3-45.1), 9 (82%) pts. remain alive. One PR pt. died secondary to cardiac complications after a hip replacement; and 1 died of progression. AEs included eight episodes of neutropenia (n=2, gr 4; n=2, gr 3; n =4, gr 2), anemia gr 2 (n=1), thrombocytopenia gr 2 (n=1), diarrhea (gr 2; n=1), nausea (gr 2, n=1), headache (gr 2; n=1), hypertension (gr 2; n=1), hypoalbuminemia (gr 2; n=1). All AEs resolved. Immune monitoring of 20 transplant pts showed a Th1 type anti-tumor immune response in responding pts. In the responders, there was a higher frequency of CD4+ICOS+PD-1+ and CD8+PD+1 T effector cells at baseline when compared to non-responding pts. In contrast, the non-responders had a Th2 type response with a higher frequency of CD4+GATA3+ T effector memory cells at baseline when compared to responders (Figure). Conclusions: Follow-up results demonstrate better than expected response rates that are durable in pts. with lymphoid malignancies who relapsed after alloSCT. Continuous remission duration was also observed after autologous SCT. Immune monitoring analysis suggests that CD4+GATA3+ T cells could be a potentially valuable biomarker for stratification of pts. for lenalodimide+ipilimumab combination therapy. Figure. Figure. Disclosures Jabbour: novartis: Research Funding.

Description: Background: Prevention or treatment of relapse after SCT for lymphoid malignancies requires novel strategies. Targeting immune checkpoints could result in lasting responses but only in few patients. Combination strategies with targeted agents, such as lenalidomide, could result in the release of tumor antigens to tumor-specific T cells. These T cells would become activated but also upregulate inhibitory checkpoints such as CTLA-4. These can be blocked with the anti CTLA-4 antibody, ipilimumab, to permit enhanced anti-tumor T cell responses (Sharma P and Allison JP. Cell 2015). In addition, the release of tumor antigens may focus the activated immune response on tumor antigens rather than self-antigens, resulting in fewer adverse events (AEs). Patients andMethods: Patients (pts.) with lymphoma or CLL who relapsed after alloSCT, with no active GVHD were eligible. Pts. with autoSCT were included within 6 months post-transplant, if they had high risk features for relapse. Treatment consisted of 4 total cycles of lenalidomide 10 mg PO daily for 21 days (cycles 1 and 3) alternating with ipilimumab 3 mg/kg IV on day 1 (Cycles 2 and 4). Lenalidomide dose reduction was permitted to 5 mg based on standard clinical practice. The primary objective was to evaluate safety and secondary objectives were to assess overall response rate (ORR) and survival. Results: Sixteen pts. were enrolled in the study. Autologous group (n=7): The median age was 55 yrs (range, 33 - 68). Lymphoma histologies included [Double-hit (DHL) (n=3), mantle cell (MCL) (n=3; including 2 with 2 prior transplants, one with CNS involvement), and Hodgkin's disease (n=1 with persistent PET+ post-SCT]. Median time to enrollment after SCT was 3.7 months. Median follow-up was 9.0 months (range, 5.3 - 27.1). All pts. remain alive. One DHL pt. transplanted during second remission relapsed at 1.6 months after just initiating cycle 2 of therapy. All others remain in complete remission (CR). The most common other AEs were 16 events of neutropenia (n=4, gr 4; n=2, gr 3, n=10, gr 2), thrombocytopenia (n=1, gr 2,) and one pt. developed pulmonary embolism on therapy. All AEs resolved. An immune-related AE occurred in one pt. (dermatitis, gr 2) after the second ipilimumab dose and resolved with steroids. Allogeneic group(n=9): The median age was 54 yrs (range, 44- 66). Histologies included [Follicular (n=3), CLL (n=2), MCL (n=2), DHL (n=1), diffuse large cell (n=1), and T-cell anaplastic lymphoma (n=1)]. The median number of therapies excluding the alloSCT was 3 (range 2- 7). Two failed a prior autoSCT, one had 2 prior alloSCT, and 3 failed prior DLIs. Two pts. relapsed within 2 months of their alloSCT prior to enrollment on study. One pt. was taken off study after cycle 1 of lenalidomide due to flare of previously diagnosed GVHD, which responded to steroids and pt. is now off immunosuppression. All others finished planned treatment without GVHD. ORR was 75% (CR 37.5% and PR 37.5%). With a median follow-up time of 9.2 months (range, 3.0-20.9), all pts. remain alive. Three pts. had recurrent disease at a median time of 5.4 months (range, 4.6 -12.0) after stopping therapy. One is showing ongoing response to retreatment. AEs included seven episodes of neutropenia (n=1, gr 4; n=2, gr 3; n =4, gr 2), anemia (n=1, gr 2), diarrhea (n=1, gr 2), nausea (n=1, gr 2), headache (n=1, gr 2), hypertension (n=1, gr 2). All AEs resolved. There were no immune mediated AEs. Immunologic analyses: We conducted 17-color flow cytometric analyses on PBMC pre-, during and post-treatment time points. We observed ~1.5-2-fold increase in ICOS+ CD4+T cells after ipilimumab+lenalidomide combination therapy. We previously identified an increase in ICOS+ CD4+ T cells as a phamacodynamic biomarker of ipilimumab therapy (Ng Tang et al., Cancer Immunology Research, 2014). Although we expected significant differences in immunologic impact of ipilimumab therapy in allogeneic versus autologous transplant pts., our preliminary data indicate similar immune responses in the two groups. Conclusions:Treatment with lenalidomide and ipilimumab after SCT for pts with lymphoid malignancies has a favorable toxicity profile. Our Immunological results, together with the fact that the frequency of AEs was not different between the allogeneic and autologous arms, suggest that combination therapy with lenalidomide and ipilimumab elicits measurable immunologic changes and clinical responses without inducing GVHD. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

Description: Neutrophil elastase (ELA2) and proteinase-3 (PRTN3) are the source proteins for the nonomeric HLA-A2-restricted peptide PR1 (VLQELNVTV), a recognized leukemia-associated antigen (LAA). In myeloid leukemia, high expression of ELA2 and PRTN3 has been correlated with improved clinical outcomes following hematopoietic stem cell transplant (HSCT). Vaccination with PR-1 peptide showed efficacy in myeloid leukemia and myelodysplastic syndrome, and was associated with immunologic response (≥ 2 fold increase in PR1-specific cytotoxic T lymphocytes (PR1-CTL)) and long-lasting clinical remissions. PR1-CTLwere shown to mediate immunity elicited by PR-1 vaccine, as they preferentially recognize and kill myeloid leukemia cells. Since ELA2 and PRTN3 have been reported in breast cancer biopsies, we hypothesized that ELA2 and PRTN3 may be mislocalized in solid tumors, leading to MHC-I presentation, therefore providing a therapeutic target for PR1 vaccine. To study the subcellular localization of ELA2 and PRTN3, the cytoplasmic, nuclear, membrane, and golgi/ER fractions were obtained from inflammatory breast cancer (IBC) (MDA-IBC1 and SUM149) and melanoma (526, 624, 888 and 926) cell lines. ELA2 was preferentially expressed in the cytoplasmic fraction in the IBC cell line SUM149, while PRTN3 was expressed in the membrane and cytoskeletal fractions of the IBC cell line MDA-IBC1. In the melanoma cell lines, ELA2 was expressed in the cytoplasmic fractions, while PRTN3 was noted in the nuclear, cytoplasmic and cytoskeletal fractions. Furthermore, the HLA-A2+ melanoma cell line 888 was susceptible to lysis by PR1-CTL (approximately 30% lysis; Effector:Target ratio=1:2). Together, these results demonstrate that ELA2 and PRTN3 are aberrantly localized in non-hematopoietic cell lines, and that this can be associated with susceptibility to PR1- CTL lysis. In particular, PR1 is a potential immunotherapeutic target for patients with melanoma and breast cancer.