Tumours switch to resist Ribas, Antoni; Tumeh, Paul C.
Nature (London),
10/2012, Letnik:
490, Številka:
7420
Journal Article
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Odprti dostop
Alternatively, broadening the immune response by combining ACT with other immune-supporting agents, such as anti-CTLA4 or anti-PD-1 antibodies, might minimize the reliance of the therapy on ...recognizing a single antigen and thereby make it harder for the cancer cells to escape. ...by identifying a mechanism by which cancers adapt to evade ACT therapy, Landsberg and colleagues have provided the basis for several testable approaches to overcome this problem in patients.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
While treatment with anti-CTLA-4 antibody can induce clinical responses in advanced cancer patients, its effects on the breadth of the T cell response is unknown. We used a next-generation ...sequencing-based method to assess T cell repertoire diversity in 46 patients with metastatic castration resistant prostate cancer or metastatic melanoma. Peripheral blood mononuclear cells were obtained from patients prior to and during treatment with anti-CTLA-4 antibody. mRNA was amplified using locus-specific primer sets for T cell receptor (TCR) beta, and the amplified product was sequenced. Sequence reads were used to quantitate absolute TCR frequencies using standardized clonotype determination algorithms with normalization by spiked reference TCR sequences. Following clonotype quantitation, repertoire differences between serial samples were assessed by the Morisita index, a statistical measure of population dispersion. 97 paired samples were assessed, of which 46 (47%) had increases and 22 (23%) had decreases in TCR diversity by more than 2-fold. By comparison, none of 9 untreated sample pairs underwent more than a 2-fold change in diversity (P = 0.005, Fisher's exact test, two tailed). TCR repertoire differences between monthly samples were markedly higher than for time-matched controls. After the first treatment, median Morisita index between samples was 0.197 for treated samples versus 0.039 for untreated (P = 0.0005, Mann-Whitney U test). The median number of clones that significantly changed in abundance was 421 for treated versus 45 for controls. In patients with multiple time points, this rapid clonotype evolution continued through treatment. Whereas the number of clonotypes that increased with treatment was not associated with clinical outcome, improved overall survival was associated with maintenance of high frequency clones present at baseline. In contrast the highest frequency clonotypes fell with treatment in patients with shorter overall survival. Stably maintained clonotypes included T cells possessing high avidity TCR such as CMV-reactive T cells. Together, these results suggest that CTLA-4 blockade induces T-cell repertoire evolution and diversification. Moreover, improved clinical outcomes are associated with less clonotype loss, consistent with the maintenance of high frequency TCR clonotypes during treatment. These clones may represent the presence of pre-existing high avidity T cells that may be relevant in the anti-tumor response.
Citation Format: Lawrence H. Fong, Edward Cha, Mark Klinger, Yafei Hou, Craig Cummings, Antoni Ribas, Malek Faham. T-cell repertoire turnover induced by anti-CTLA-4 antibody treatment in cancer patients. abstract. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5017. doi:10.1158/1538-7445.AM2014-5017
Abstract
BRAF inhibitor targeted therapies such as vemurafenib (PLX4032) or dabrafenib, block BRAFV600 driver oncogenic mutations and result in high initial response rates and improve survival in ...patients with melanoma. Although response rate is over 50%, resistance eventually develops. A possible explanation is established tumors escape supported by the immune suppressive tumor-infiltrating myeloid cells (TIMs) including M2 type macrophages and myeloid derived suppressor cells (MDSC).
Our murine melanoma SM1 model that harbors BRAFV600 mutation is an aggressive model, where mice with established tumors have to be sacrificed within two-three weeks. Treatment with PLX4032 has significant anti-tumor effect, but it cannot fully eradicate the tumor. In addition, our prior results show that SM1 is infiltrated by M2-polarized macrophages. By depleting TIMs with the CSF-1R inhibitor, PLX3397, the tumor infiltrating lymphocytes (TILs) is increased. To determine if combined therapy with PLX3397 and PLX4032 improved anti-tumor responses against SM1 tumors, C57BL/6 mice with established subcutaneous SM1 tumors received oral gavage daily with PLX3397 (50mg/kg) and i.p. daily with PLX4032 (100mg/kg). Combined treatment demonstrated superior effects compared to either of single treatment (tumor size on day 12_vehicle: 862.0±17.0 mm2, PLX3397: 439.3±6.9 mm2, PLX4032: 113.7±2.6 mm2, PLX3397+PLX4032: 12.9±4.6 mm2, p<0.05). When SM1 tumors were implanted in immunodeficient NSG mice treated with PLX3397 and PLX4032, the superior anti-tumor effect of the combined group disappeared and its tumor growth overlapped with PLX4032 treated group (tumor size on day 15_vehicle: 1432.9±46.2 mm2, PLX3397: 1374.6±41.4 mm2, PLX4032: 1080.0±30.0 mm2, PLX3397+PLX4032: 1028.3±49.0 mm2, p>0.05). To further confirm that combined treatment effect is mediated by CD8+ T-cells, SM1 tumors were implanted in immunocompetent C57BL/6 mice and treated with PLX3397, PLX4032, and anti-CD8 neutralizing antibody. The anti-tumor response in PLX3397, PLX4032, and anti-CD8 antibody group was greatly diminished (tumor size on day 16_vehicle: 751.6±12.2 mm2, PLX4032: 232.4±8.8 mm2, anti-CD8: 722.8±12.5 mm2, PLX3397+PLX4032: 101.0±7.6 mm2; PLX3397+PLX4032+anti-CD8: 442.0±5.7 mm2, p>0.05).
In conclusion, our data from SM1 in vivo model combining CSF-1R blockade and BRAF oncogenic blockade supports the rationale for testing this combination in patients with advanced melanoma, and suggest that the benefit is mediated by anti-tumor T cells. This combination is now in clinical testing (NCT01826448).
Citation Format: Stephen Mok, Richard Koya, Jennifer Tsoi, Lidia Robert, Jesse Zaretsky, Christopher Tsui, Thomas Graeber, Antoni Ribas. Improving antitumor effects of a BRAF inhibitor with a colony stimulating factor 1 receptor (CSF-1R) inhibitor, PLX3397. abstract. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 147. doi:10.1158/1538-7445.AM2014-147
Previous investigations identified transcriptional signatures associated with innate resistance to anti-programmed cell death protein 1 therapy in melanoma. This analysis aimed to increase ...understanding of the role of baseline genetic features in the variability of response to BRAF and MEK inhibitor therapy for
-mutated metastatic melanoma.
This exploratory analysis compared genomic features, using whole-exome and RNA sequencing, of baseline tumors from patients who had complete response versus rapid progression (disease progression at first postbaseline assessment) on treatment with cobimetinib combined with vemurafenib or vemurafenib alone. Associations of gene expression with progression-free survival or overall survival were assessed by Cox proportional hazards modeling.
Whole-exome sequencing showed that
and
alterations were more frequent in tumors from patients with rapid progression, while
alterations were more frequent in tumors from patients with complete response. However, the low frequency of alterations in any one gene precluded their characterization as drivers of response/resistance. Analysis of RNA profiles showed that expression of immune response-related genes was enriched in tumors from patients with complete response, while expression of keratinization-related genes was enriched in tumors from patients who experienced rapid progression.
These findings suggest that enriched immune infiltration might be a shared feature favoring response to both targeted and immune therapies, while features of innate resistance to targeted and immune therapies were distinct.
Abstract only
9507
Background: First-line treatment with D+T demonstrated prolonged progression-free survival (PFS) and overall survival (OS) in patients with BRAF V600–mutant unresectable or ...metastatic melanoma. With 5 years of follow-up, we report survival and describe characteristics of patients in the phase 3 COMBI-d and COMBI-v trials with long-term benefit. Methods: Pooled 5-year landmark data for patients treated with D+T in the phase 3 COMBI-d (NCT01584648) and COMBI-v (NCT01597908) trials were analyzed. The trials enrolled patients with previously untreated BRAF V600E/K–mutant unresectable or metastatic melanoma. Patients received D 150 mg twice daily plus T 2 mg once daily vs either D + placebo (COMBI-d) or vemurafenib (COMBI-v). The primary endpoints were PFS in COMBI-d and OS in COMBI-v. Results: The pooled population included 563 patients who received D+T (COMBI-d, n = 211; COMBI-v, n = 352). Four- and 5-year PFS and OS rates were similar, suggesting a stabilization (4- and 5-year PFS, 21% 95% CI, 17%-24% and 19% 95% CI, 15%-22%, respectively; 4- and 5-year OS, 37% 95% CI, 33%-42% and 34% 95% CI, 30%-38%, respectively). In patients with normal baseline lactate dehydrogenase (LDH) levels the 5-year PFS rate was 25% vs 8% in patients with elevated baseline LDH levels. Similarly, the 5-year OS rate was considerably higher in patients with normal baseline LDH levels vs those with elevated LDH levels at baseline (43% vs 16%). Among patients with normal baseline LDH levels and < 3 organ sites with metastases, the 5-year PFS and OS rates were 31% and 55%, respectively. In addition, exploratory analyses will be performed to characterize subgroup(s) of patients most likely to experience long-term benefit. Of 299 patients who received subsequent anticancer therapy following treatment with D+T, 151 (51%) received an anti–CTLA-4 therapy and 102 (34%) received an anti–PD-1 therapy. The safety profile of D+T was as previously reported, and no new safety signals were observed. No treatment-related deaths were reported. Conclusions: First-line treatment with D+T leads to durable long-term benefit in many patients with BRAF V600–mutant unresectable or metastatic melanoma. Clinical trial information: NCT01584648; NCT01597908.
Abstract only
9531
Background: Checkpoint inhibitors and targeted therapies have improved outcomes in pts with BRAF V600–mutant advanced melanoma; however, many pts progress and new treatment (tx) ...strategies are needed. BRAF inhibition increases T-cell infiltration, melanoma antigen expression, and PD-1/PD-L1 expression, which may lead to synergistic activity with anti–PD-1 therapy. Methods: COMBI-i is investigating first-line S 400 mg Q4W + D 150 mg BID + T 2 mg QD in pts with unresectable or metastatic BRAF V600–mutant melanoma (NCT02967692). Here we report pooled efficacy and safety data from parts 1 (run-in cohort) and 2 (biomarker cohort). Response was assessed per RECIST v1.1. Results: 36 pts were enrolled (part 1: n = 9; part 2: n = 27); 18 (50%) had stage IV M1c and 15 (42%) had elevated LDH levels. At the data cutoff (median follow-up, 15.2 mo), tx was ongoing in 17 pts (47%). The confirmed objective response rate (ORR) by investigator assessment was 75% (n = 27), with 33% complete responses (CRs; n = 12). Medians for duration of response (DOR; 7/27 pts with events), progression-free survival (PFS; 13/36 pts with events), and overall survival (OS; 7/36 pts with events) were not reached. 12-mo DOR rate was 71.4% (95% CI, 49%-85%). 12-mo PFS and OS rates were 65.3% (95% CI, 47%-79%) and 85.9% (95% CI, 69%-94%), respectively. In pts with high baseline LDH: ORR was 67%, with 3 CRs (20%), median PFS was 10.7 mo (events in 10/15 pts 67%), and median OS was not reached, with events in 6/15 pts (40%). All pts had ≥ 1 AE; 27 (75%) had grade ≥ 3 AEs. 6 pts (17%) had AEs leading to discontinuation of all 3 study drugs. Any-grade AEs in ≥ 40% of pts included pyrexia, chills, fatigue, cough, and arthralgia. Grade ≥ 3 AEs in > 3 pts were neutropenia, pyrexia, and increased lipase. One pt died of cardiac arrest that was not considered related to study tx. Conclusions: S+D+T showed promising and durable ORR (75%) with CR in 33% of pts. With > 15 mo of follow-up, median PFS was not reached. The safety profile was manageable reflecting individual toxicities of D, T, and S. The global, placebo-controlled, randomized phase 3 (part 3) of COMBI-i is ongoing. Clinical trial information: NCT02967692.
Abstract only
9515
Background: Although pts with both low tumor mutation burden (TMB) and T-cell–inflamed gene expression profiles (TI-GEPs) usually have poor outcomes with anti–PD-1 therapy, an ...analysis in the adjuvant melanoma setting suggested that these pts benefited from adjuvant D+T therapy. Here we analyze TMB/TI-GEPs and other biomarkers in pts receiving a combination of anti–PD-1 and D+T therapy. Methods: The phase 3 COMBI-i study (NCT02967692) is evaluating S in combination with D+T in previously untreated pts with BRAF V600–mutant unresectable/metastatic melanoma. In the safety run-in (part p 1) and biomarker (p2) cohorts, blood/tissue samples were collected at baseline (BL), after 2-3 and 8-12 wk of treatment, and at disease progression. TMB/circulating tumor DNA (ctDNA) and TI-GEPs were examined by targeted DNA-seq and RNA-seq, respectively. Results: At data cutoff, 6 of 22 pts with DNA- and RNA-seq data available had a PFS event. At BL, these pts had low TMB, low TI-GEPs (4 of 6), or high levels of immunosuppressive TME signatures (eg, fibroblast, M2 macrophages) vs pts without a PFS event. Elevated BL ctDNA was significantly associated with PFS events ( P< .001). Pts with a complete response (CR) on S+D+T had significantly lower levels of BL immunosuppressive TME signatures (eg, M2 macrophages; P< .01) than pts without a CR. We observed a consistent increase in TI-GEPs and decrease in MAPK pathway activity score (MPAS) from BL to biopsy at 2-3 wk in all pts regardless of subsequent progression. Pts with a PFS event and available longitudinal biomarker data were characterized by a subsequent decrease in TI-GEPs and an increase in MPAS per the 8- to 12- wk biopsy sample. Conclusions: These results suggest that S+D+T had an early impact on tumor cells and the TME, potentially promoting antitumor activity. The majority of PFS events occurred in the TMB-low/TI-GEP-low subgroup. An immunosuppressive TME might preclude early CRs. The predictive implications of coupling TMB/GEP subgroups with other TME marker subgroups need further validation. The randomized placebo-controlled p3 of COMBI-i is ongoing. Clinical trial information: NCT02967692.
Abstract only
9555
Background: SD-101 is a synthetic CpG-ODN agonist of TLR9 that stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells - activating T cell ...anti-tumor responses. Pembrolizumab has demonstrated activity in melanoma. SYNERGY-001/KEYNOTE-184 study assesses the safety and preliminary efficacy of the combination of intratumoral SD-101 and intravenous pembrolizumab in PD1/PDL 1 resistant unresectable stage IIIC- IV melanoma. A prior phase 2 study with SD-101 at 8 mg per injection resulted in a 21.4% ORR in this population (Abstract 3781, ESMO 2018). We report preliminary data in this ongoing phase 2 trial evaluating efficacy at a lower SD-101 dose of 2 mg per injection. Methods: PD1/PDL 1 resistant melanoma patients received 2 mg of SD-101 intratumorally per lesion in 1-4 lesions (weekly x 4 doses followed by Q3W x 7). Pembrolizumab was administered at a dose of 200 mg intravenously Q3W. Scans were performed Q9W. Responses were assessed per RECIST v1.1. Results: 23 patients have been enrolled with baseline characteristics: median age 65 years; male: 77%; stage at screening: IIIC = 26%; IV = 57%, unknown = 17%; LDH > ULN: 36%. Lines of prior therapy: 1: 52%; 2: 22%; > 2: 26%. Prior anti CTL-A4 therapy: 39%. Best overall response on prior antiPD-1/PD-L1: PD: 88%, PR/CR: 8%, SD: 4%. Safety: Grade ≥3 treatment-related AEs: pneumonia and constipation (8%). No immune-related AEs reported. 2 non-treatment related SAEs reported from 2 patients: pneumonia and intussusception. 4 patients discontinued treatment early: 1 post SAE, per patient’s request, 3 due to PD. 1 patient died due to malignant pleural effusion after 1 dose of SD 101 and Pembrolizumab. No treatment related deaths. Efficacy: Mean duration on treatment: 39 days (1 - 169). mITT population: six patients at time of first CT scan at day 64: PR: 1, SD: 1, PD:3; non-evaluable: 1. 17 patients on study have not yet had first CT scan. Conclusions: The TLR9 innate immune stimulant, SD-101, in combination with pembrolizumab is well tolerated. Mature efficacy data, with additional first and second follow-up CT scans, will be presented at the meeting. Clinical trial information: NCT02521870.
MAPK-targeting in cancer often fails due to MAPK-reactivation. MEK inhibitor (MEKi) monotherapy provides limited clinical benefits but may serve as a foundation for combination. Here, we showed that ...combining a type II RAFi with an allosteric MEKi durably prevents and overcomes acquired resistance among cancers with
KRAS, NRAS, NF1, BRAF
non-V600
and
BRAF
V600
mutations. Tumor cell-intrinsically, type II RAFi plus MEKi sequester MEK in RAF complexes, reduce MEK/MEK dimerization, and uncouple MEK from ERK in acquired-resistant tumor subpopulations. Immunologically, this combination expands memory and activated/exhausted CD8
+
T-cells, and durable tumor regression elicited by this combination requires CD8
+
T-cells, which can be reinvigorated by anti-PD-L1 therapy. Whereas MEKi reduces dominant intra-tumoral T-cell clones, type II RAFi co-treatment reverses this effect and promotes T-cell clonotypic expansion. These findings rationalize the clinical development of type II RAFi plus MEKi and their further combination with PD-1/L1-targeted therapy.
Tumor antigen genetically modified dendritic cells (DC) have been extensively tested as cancer vaccine approaches in preclinical models. This testing has provided evidence of their ability to ...generate coordinated antitumor CD8+ cytotoxic T lymphocyte (CTL) and CD4+ T-helper cell responses. Their antitumor activity compared favorably to multiple other vaccination strategies in mice. This approach has been brought to patients within nine pilot clinical trials reported to date. These clinical trials have tested both RNA and DNA as means to introduce the foreign genetic material into the DC. Administration to human subjects has proven to be both feasible and safe. There is clear evidence of the ability to activate both CD8+ CTL and CD4+ T-helper cells, which has been the major scientific endpoint in most of these trials. However, antitumor activity has been marginal thus far. In conclusion, tumor antigen genetically modified DC are a feasible strategy to activate tumor-specific T cells in humans.
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