Melanoma & CD8 Killer T Cells

Melanoma & CD8 Killer T Cells
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INT230-6 is an early phase dose-escalation study first in hand study evaluating effectiveness of a new compound called PORT-2 now PORT-2 is an invariant natural killer T cell agonist so iNKT cells are sort of a small but important part of the immune system having influence over a number of parts and activated ion key T cells we know have positive effects upon antigen presenting cells which then in turn drives some CD8 T cell responses which are key things in anti-tumorresponses they also promote hearts the effectiveness of natural killer T cells they can also bind directly to tumorcells which increases the expression of checkpoint inhibitors allowing such treatments to be to work hand-in-hand with other treatments invariant natural killer T cells can also have a favorable impact upon a tumorenvironment making it less immunosuppressive and again allowing treatments to become more effective so in this study what we have done is we have given port two  so far administered it to five patients in two dose levels  and thus far we have seen a  number of positive  findings and specifically the drug has been well tolerated to date we haven't seen any DLTS or SAPs I'm just a series of acceptable grade one and grade two toxicities  the five patients that have been tested so far we've seen a mixed response in a  in a patient pre-treated sorry a patient with melanoma who had been previously pre-treated with all standard therapies including target therapies and immunotherapy we are at the point of hopefully moving soon to testing a third dose level of port two and  once we have our dose we will test that in further safety cohort and then we have plans to move on to a phase to study if I can just backtrack a little bit i realized I’ve got to say that this port two or three IMP-MEL is targeting patients with non-small cell lung cancer and advanced melanoma to two populations where we already know that immunotherapy has a as a role in the aim of  IMP-MEL is to see import two can improve the effectiveness of immunotherapy in these metabolic groups.

Both of these tumortypes have a number of a number of challenges but one of the biggest ones is the fact that despite advances in treatment options there is still most patients who will not benefit and eventually progress so melanoma in patients with melanoma close to 50 percent of patients will eventually progress despite having optimal immunotherapy treatment and lung normal cell lung cancer that figure is sadly higher and so there's a big unmet need and a drive to try and work out why there are these significant proportions of patients who are not responding to treatments understanding. these mechanisms and developing drugs that can improve these responses and potentially long-term with long-term benefits for these patients.

Will This Affect Clinicians Today?

so at the moment as an early phase study, there'll be no immediate impact but I think this our results our data has shown that this novel approach using an ink T cell agonist that has an impact upon multiple arms of the immune system  has the potential to interact favorably with existing treatments and improve outcomes  data so far as mentioned before showing that's reasonably well tolerated and we hope this generates some interest as I mentioned before we're going to move into a phase two study soon where we'll compare the effectiveness of port two  with pembrolizumab versus pimp realism up alone and we plan to expand to a number of sites and we'll be after patients so hopefully some of some interest or excitement generated from this will result in clinicians referring as patients and giving them an opportunity to participate in the study

What Are The Next Steps?

so the next step in the research will be to complete the dose-escalation phase so we're almost there we're going to move on to the third dose level soon in parallel with that we'll obtain more of our biomarker data so we're testing for a number of important cytokines which are reflective of overall immune response we're also taking tumorbiopsies as well looking for things like T cell repertoire and ptl1 expression and that information will be of course very interesting once we complete the three-dose levels we'll then take the selected dose and test it in combination with pembrolizumab and once we hopefully demonstrate that that can be safely administered we then will move on to a phase two study where we will be testing the effect of adding port two parameters app so you know the arms of the study will be primarily isolate alone versus Pembrolizumab with 0.2 and this will be tested in patients untreated patients with metastatic non-small cell lung cancer and melanoma and hopefully we will see a difference

Final Thoughts

I think it's important for people to appreciate that there are other elements other potential targets of the immune system to try and focus on  apart from checkpoint inhibitors so much of the current research landscape and immunotherapy is looking at new checkpoints and this is proving very productive but  what we're doing here is I guess focusing on a broader element which has an impact across multiple arms of the immune system adaptive innate and the microenvironment and hopefully by doing that we'll identify a product that will work in concert with existing therapies.

 

Nicholas Coupe, MBBS, Oncologist at Oxford University Hospitals NHS Foundation Trust. In this video, he speaks about the ASCO 2022 abstract - A phase 1 first-in-human dose-finding/randomized phase 2 study of IMM60 and pembrolizumab (PEM) in advanced melanoma and non–small cell lung cancer (NSCLC; IMP-MEL).

 

Origins:

 

Invariant natural killer T-cells (iNKTs) exhibit characteristics of both innate cells (NK-like) and T-cells (can prime and boost an adaptive immune response). The importance of this relatively rare lymphocyte subset has increased due to its dual potential to have a direct cytotoxic effect on CD1d expressing malignancies as well as its ability to induce long-lasting anticancer CD8 T cell responses mediated through dendritic cell cross-priming and licensing. Several therapeutic techniques including the use of allogenic iNKT cells (both untransduced and CARs) are being developed, and we describe preliminary clinical investigations with IMM60, a synthetically produced iNKT cell agonist formulated in a liposome ( PORT-2). In preclinical investigations, IMM-60 administration resulted in DC and B cell maturation as well as strong activation of iNKT cell-derived IFN-g. IMM60 displayed monotherapy activity in PD-1 resistant models (e.g., B16-F10), up-regulation of PD-L1 expression on cancer cells as a result of its priming effect, and the ability to overcome resistance to PD-1 antibody therapy in efficacy tests.

 

Methodology:

 

IMP-MEL is a phase 1/2 open-label research presently enrolling adult patients with advanced NSCLC and melanoma. IMM60 liposomes were given IV Q3W at three ascending dose levels for six doses alone or with PEM 200mg Q3W. The purpose of the study is to evaluate the safety and efficacy of IMM-60 alone and in combination with PEM. Results: Five participants were included in the monotherapy cohort, with a median of three prior treatments (min 2, max 5). The average age was 64.5 years. To yet, no treatment-related adverse events or objective disease responses have been documented in the evaluable monotherapy individuals (n=3).

 

Findings:

 

At the levels examined, IMM-60 is well tolerated when provided IV as monotherapy. The liposomal formulation has a promising preliminary safety profile. The full phase 1 results, including circulating cytokine and flow cytometric analyses, will be presented during the symposium. The experiment will proceed to phase 2 comparing IMM60 alone versus PEM monotherapy versus the combination of IMM60 and PEM.