ipi/nivo efficacy in melanoma brain mets, CD8+ T cell actions, and (surprise, surprise!!!) CONCURRENT radiation and immunotherapy is even better in brain mets

I've only said most of this post a zillion times.  Brain mets suck great big hairy green wizard balls!!! We know immunotherapy works in the brain and body.  AND...we KNOW that immunotherapy combined with radiation works even better for brain mets.  But...we begin again...

We'll start with a bit of relatively new information at the cellular level:

Anti-PD-1/anti-CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8+ T cell trafficking. Taggart, Andreou, Scott, et al.  Proc Natl Acad Sci U S A. 2018 Jan 31.

Inhibition of immune checkpoints programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) on T cells results in durable antitumor activity in melanoma patients. Despite high frequency of melanoma brain metastases (BrM) and associated poor prognosis, the activity and mechanisms of immune checkpoint inhibitors (ICI) in metastatic tumors that develop within the "immune specialized" brain microenvironment, remain elusive. We established a melanoma tumor transplantation model with intracranial plus extracranial (subcutaneous) tumor, mimicking the clinically observed coexistence of metastases inside and outside the brain. Strikingly, intracranial ICI efficacy was observed only when extracranial tumor was present. Extracranial tumor was also required for ICI-induced increase in CD8⁺ T cells, macrophages, and microglia in brain tumors, and for up-regulation of immune-regulatory genes. Combined PD-1/CTLA-4 blockade had a superior intracranial efficacy over the two monotherapies. Cell depletion studies revealed that NK cells and CD8⁺T cells were required for intracranial anti-PD-1/anti-CTLA-4 efficacy. Rather than enhancing CD8⁺ T cell activation and expansion within intracranial tumors, PD-1/CTLA-4 blockade dramatically (∼14-fold) increased the trafficking of CD8⁺ T cells to the brain. This was mainly through the peripheral expansion of homing-competent effector CD8⁺ T cells and potentially further enhanced through up-regulation of T cell entry receptors intercellular adhesion molecule 1 and vascular adhesion molecule 1 on tumor vasculature. Our study indicates that extracranial activation/release of CD8⁺ T cells from PD-1/CTLA-4 inhibition and potentiation of their recruitment to the brain are paramount to the intracranial anti-PD-1/anti-CTLA-4 activity, suggesting augmentation of these processes as an immune therapy-enhancing strategy in metastatic brain cancer.

OK....so that sounds important and impressive.  Now, there's this, which probably explains a bit of the above:

CD103+ tumor-resident CD8+ T cells are associated with improved survival in immunotherapy naive melanoma patients and expand significantly during anti-PD1 treatment. Edwards, Wilmott, Madore, et al.Clin Cancer Res. 2018 Mar 29.

Therapeutic blockade of immune checkpoints has revolutionized cancer treatment. Durable responses however, occur in less than half of those treated and efforts to improve treatment efficacy are confounded by a lack of understanding of the characteristics of the cells that initiate anti-tumor immune response.  

We performed multi-parameter flow cytometry and quantitative multiplex immunofluorescence staining on tumor specimens from immunotherapy-naïve melanoma patients and longitudinal biopsy specimen obtained from patients undergoing anti-PD-1 therapy.

Increased numbers of CD69+CD103+ tumor-resident CD8+ T cells was associated with improved melanoma-specific survival in immunotherapy-naive melanoma patients. Local IL-15 expression levels strongly correlated with these tumor-resident T cell numbers. The expression of several immune checkpoints including PD-1 and LAG3 was highly enriched in this subset and these cells significantly expanded early during anti-PD-1 immunotherapy. 

Conclusions: Tumor-resident CD8+ T cell numbers are more prognostic than total CD8+ T cells in metastatic melanoma. In addition, they are likely to initiate response to anti-PD-1 and anti-LAG-3 treatments. We propose that the immune profile of these cells prior to treatment could inform strategies for immune checkpoint blockade.

Ok.  That is good to know!  Now...how to we make that happen?????

And of course...no melanoma brain met post is complete unless I'm yelling!!!!  So here are a zillion posts about the benefit of immunotherapy COMBINED with radiation for brain mets:

CONCURRENT radiation and immunotherapy for brain mets is BEST!!!! (yes, AGAIN!!!)

And yes...there is this shocking finding!!!  The ipi/nivo combo is better in treating melanoma in the brain than nivo alone!!!  AGAIN!!!  (Just like in the body....sigh....)

Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Long, Atknson, Lo, et al.  Lancet Oncol. 2018 Mar 27.

Nivolumab monotherapy and combination nivolumab plus ipilimumab increase proportions of patients achieving a response and survival versus ipilimumab in patients with metastatic melanoma; however, efficacy in active brain metastases is unknown. We aimed to establish the efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with active melanoma brain metastases.

This multicentre open-label randomised phase 2 trial was done at four sites in Australia, in three cohorts of immunotherapy-naive patients aged 18 years or older with melanoma brain metastases. Patients with asymptomatic brain metastases with no previous local brain therapy were randomly assigned using the biased coin minimisation method, stratified by site, in a 30:24 ratio (after a safety run-in of six patients) to cohort A (nivolumab plus ipilimumab) or cohort B (nivolumab). Patients with brain metastases in whom local therapy had failed, or who had neurological symptoms, or leptomeningeal disease were enrolled in non-randomised cohort C (nivolumab). Patients in cohort A received intravenous nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg every 3 weeks for four doses, then nivolumab 3 mg/kg every 2 weeks; patients in cohort B or cohort C received intravenous nivolumab 3 mg/kg every 2 weeks. The primary endpoint was intracranial response from week 12. Primary and safety analyses were done on an intention-to-treat basis in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, number NCT02374242, and is ongoing for the final survival analysis.

Between Nov 4, 2014, and April 21, 2017, 79 patients were enrolled; 36 in cohort A, 27 in cohort B, and 16 in cohort C. One patient in cohort A and two in cohort B were found to be ineligible and excluded from the study before receiving the study drug. At the data cutoff (Aug 28, 2017), with a median follow up of 17 months (IQR 8-25), intracranial responses were achieved by 16 (46%) of 35 patients in cohort A, five (20%; 7-41) of 25 in cohort B, and one (6%; 0-30) of 16 in cohort C. Intracranial complete responses occurred in six (17%) patients in cohort A, three (12%) in cohort B, and none in cohort C. Treatment-related adverse events occurred in 34 (97%) of 35 patients in cohort A, 17 (68%) of 25 in cohort B, and eight (50%) of 16 in cohort C. Grade 3 or 4 treatment-related adverse events occurred in 19 (54%) patients in cohort A, four (16%) in cohort B, and two (13%) in cohort C. No treatment-related deaths occurred.

Nivolumab combined with ipilimumab and nivolumab monotherapy are active in melanoma brain metastases. A high proportion of patients achieved an intracranial response with the combination. Thus, nivolumab combined with ipilimumab should be considered as a first-line therapy for patients with asymptomatic untreated brain metastases.

Why in the world the poor folks in Cohort C had to get the shaft TWICE, I don't know!!  Once in being the poor peeps who had already failed a therapy and/or had symptomatic disease and secondly by being given the less effect treatment....DAMN!  Anyhow, as usual, I digress...  So folks with untreated brain mets with no symptoms were put into two groups.  Group A got ipi/nivo and 46% gained a response.  Group B got nivo alone and attained a 20% response rate.  And as noted, the folks with symptoms and/or had already failed one treatment for their brain mets were put into Group C and given nivo only, where they had only 1 response in their n=16.  So...small numbers here...and to me this serves only as reinforcement for what we already know: YES!!!! Immunotherapy works in the brain!!!!  (BUT....even better WITH SRS or gamma knife radiation therapy....circle back to above!!!!)

For what it's worth... - c