Search Results for: 4-1BB

Targeting TNFRs with agonist antibodies for cancer therapy: 4-1BB, GITR, CD27

#ASCO14, 4-1BB, biologics, CD27, CLDX, GITR, immunotherapy, Merck, monoclonal antibodies, OX40, Pathways for Drug Development, Pfizer, TNF receptors

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One of the puzzles in thinking about the available costimulatory receptors on T cells (and NK cells) is the unsettling number of them. Sticking just to the TNF receptor superfamily (TNFRSF) we have OX40 (discussed earlier), 4-1BB, GITR, CD27, and also the TNF receptors themselves (1 and 2), the lymphotoxin beta-receptor, HVEM, and TNFRSF25. There may be some I’ve forgotten. As noted in part 1 OX40, GITR, 4-1BB and CD27 are evolutionary cousins, as are their cognate ligands. Why did the immune system evolve such a complexity of T cell costimulators?

The answer is not entirely clear although the expression patterns and kinetics of expression suggest some rationale for understanding the number of different receptors. Also, as it’s understood that all the TNF receptors signal via NF-kB, Jun and p38, we might see these receptors either compete (for signaling proteins) or cooperate. All of the available genetic and pharmacologic data suggest they cooperate or even synergize, thereby powering the T cell response when needed. Since T cell responses (and immune responses generally) are so dangerous when dysregulated, the multiplicity of on and off switches presumably allows for redundancy of control.

As we said previously, OX40 comes on slow and easy, starting about 12 hours after TCR stimulation, and riding along for up to 96 hours. This is in vitro, cell culture data … so lets recognize that in vivo, in response to the chaotic presentation of antigen, the population of T cells is likely to be turning over, proliferating … so it’s unlikely we will see a finely tuned kinetic response in the real world, as regards the population of responding cells. Nonetheless we can focus on a single T cell, just the one. And we’ve guessed it will be expressing OX40 say from day 2 to day 5 after activation. Lets …

A few things I Iearned in 2020: an immune-oncology perspective

Aleta Biotherapeutics, CAR T cells, immuno-oncology, immunology, immunotherapy, oncology, Pathways for Drug Development, PD-1

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Teaching immune cells how to kill, and other things I learned in 2020
Therapeutics and targets mentioned: 4-1BB, Bispecific-engagers, CAR-T, CD39/CD73/A2AR, CD47, FcαRI, FcγRIIa, Flt3L, GM-CSF, IL-2, Immune Checkpoints, LILBR2/ILT-4, OX40, PD-1, Siglec10/CD24, STING, TIGIT/DNAM-1, TIL, TLR7/8  & 9.
Companies mentioned: Agenus, Aleta Biotherapeutics, Alkermes, Alligator, Apexigen, AstraZeneca, Celldex, GSK, IgM Biosciences, I-Mab, Immune-Onc, Iovance, Jounce, Merck, Nektar, Seagen, Roche.
Two talks given at SITC 2019 session set me thinking about the quality of immune cell interactions, the outcomes for the interacting cells and the implications for cancer immunotherapy. These talks, by Ron Germain and Michael Dustin, presented the lives of immune cells in a series of diverse locations with a complex cast of characters.  Learnings regarding immune geography and cell:cell contact are increasingly important as we consider how best to advance cell therapies for diverse hematologic malignancies and solid tumors (www.aletabio.com).
These investigators work to understand the cell biology that supports a productive immune encounter, and this depends in part on location as much as it does on cell type. The bio-pharma field has focused on T cells as the major target cell type for cancer immunotherapy, but it is clear that B cells, myeloid cells, dendritic cells, NK cells and neutrophils can play unique and critical roles.  Immunology insights gained in 2020 will influence how we think about immune-checkpoint therapeutics, cell therapeutics and tumor resistance to therapy.  Historically, we can link these lessons back to two of the very earliest “applied” immune-therapeutics, the cytokines IL-2 and GM-CSF, that trigger distinct subsets of immune cells.
Part 1: Location, location, location.
In January 2020 four papers were published that described the correlation between the presence of tertiary lymphoid organs and B cells with successful immune checkpoint therapy in diverse cancer indications (see here).  This was an interesting finding and one that I think remains under-appreciated by …

T cell fitness and genetic engineering

4-1BB, Chimeric Antigen Receptor, CRISPR/Cas9, genetic engineering, immuno-oncology, immunotherapy, oncology, TGF beta,

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This is a subject we have been thinking about in great detail and this publication in Cell was a trigger for me to start organizing those thoughts. Here is the full reference to the paper discussed: In press, Roth et al., Pooled Knockin Targeting for Genome Engineering of Cellular Immunotherapies, Cell (2020).
My thanks to Mark Paris from Daiichi Sankyo for his tip to read this paper.

This publication (https://doi.org/10.1016/j.cell.2020.03.039) is by Theodore Roth and colleagues from Alexander Marson’s lab at UCSF.  They present a nice technological advance, the development of a process by which a pool of genes are knocked into a locus, allowing one to examine the consequence of altering the responsiveness of a cell, in this case, a T cell. This type of work springs from a long lineage of genetic manipulation strategies, from random mutagenesis, to random then targeted gene knockouts (in cells and animals) and gene knockins (what we once called transgenics) and elegant gene-editing technologies (gene therapy, CRISPR/Cas-9, cell therapy, gene-delivery) and so on.
The focus in this paper is on optimizing T cell activity in the setting of solid tumors, something we think about every waking hour at Aleta Biotherapeutics (www.aletabio.com). So, let’s see what we’ve got here.
The pooled knockin strategy relies on two key elements – DNA barcoding, a well-developed technology that has its roots in high throughput library screening technologies, and locus targeting via HDR, which can be achieved using CRISPR/Cas9 and guide templates. Put these two things together and you now have the ability to mix and match genes of interest (following these via their specific barcodes) and place then into the desired locus – here that locus is the TRAC (the TCR locus). They also knocked in a defined TCR (for NY-ESO-1). So, this is a nice system with a known TCR and various …

New Horizons Across the Immunotherapy Landscape – Lymphoid Structures Drive Immune Checkpoint Therapy and the Efficacy of Cellular Therapeutics

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We’d been hearing the rumors for months. But the simultaneous publication in Nature of three papers describing a critical role for lymphoid structures and B cells in supporting T cell anti-tumor immunity was a remarkable milestone in our evolving understanding of immuno-oncology. Really stunning work. Importantly, these papers fit into a new contextual framework and cap a series of studies that have come out over the last year or so that have enriched our understanding of how the immune system and tumor cell populations interact. This broader and still evolving contextual framework will impact immunotherapy drug development across the immune checkpoint field, the tumor vaccine space, innate immune approaches, the T-cell-directed biologics, and cellular therapies.
But first, these new papers are gorgeous:
The study presented by Petitprez et al. is focused on the response of sarcomas to immunotherapy (https://www.nature.com/articles/s41586-019-1906-8). The soft tissue sarcomas (STS) have mixed clinical responses to immune checkpoint blockade (ICB) treatment, and it is not clear what drives the variable response. In general, STS have been classified as having a low tumor mutational burden (TMB) and are considered non-immunogenic, or ‘cold’, and have little expression of PD-L1. A few STS subtypes are characterized by more complex genetic abnormalities and could potentially have more actionable mutations for the immune system to recognize. Regardless, two of most widely used biomarkers of ICB response (TMB-high or PD-L1-positive) are not generally relevant in STS. In this study, gene expression profiling was used to examine patterns of ICB response in patients across a wide variety of STS subtypes and pathologies. Three distinct genetic classes were identified that match known tumor microenvironments (TME) – immune desert (A), highly vascular (C), and inflamed (E) with two intermediates: B and D. These are well understood classifications and mirror many prior studies of the TME and ICB response and …

Radical optimism: considering the future of immunotherapy

#SITC18, cancer, immuno-oncology, immunotherapy, oncology, Pathological Cells and Processes, Pathways for Drug Development, tumor microenvironment, Uncategorized

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I wrote recently about the sense of angst taking hold in the next-generation class of immuno-therapeutics – those targets that have come after the anti-CTLA4 and anti-PD-(L)-1 classes, and raised the hope that combination immunotherapy would broadly raise response rates and durability of response across cancer indications.
There are diverse next-generation immuno-therapeutics including those that target T cells, myeloid cells, the tumor stromal cells, innate immune cells and so on. A few examples are given here (and note that only a few programs are listed for each target):

There are of course many other therapeutic targets – OX40/CD134, Glutaminase, ICOS, TIM-3, LAG-3, TIGIT, RIG-1, the TLRs, various cytokines, NK cell targets, etc.
In the last year – since SITC 2017 – there has been a constant stream of negative results in the next generation immuno-therapy space, with few exceptions. Indeed, each program listed in the table has stumbled in the clinic, with either limited efficacy or no efficacy in the monotherapy setting or the combination therapy setting, typically with an anti-PD-(L)-1 (ie. an anti-PD-1 or an anti-PD-L-1  antibody). This is puzzling since preclinical modeling data (in mouse models and with human cell assays) and in some cases, translation medicine data (eg. target association with incidence, mortality, or clinical response to therapy), suggest that all of these targets should add value to cancer treatment, especially in the combination setting. I’ve discussed the limitations of these types of data sets here, nonetheless the lack of success to date has been startling.
With SITC 2018 coming up in a few days (link) I think it is a good time to step back and ask: “what are we missing?”
One interesting answer comes from the rapidly emerging and evolving view of tumor microenvironments (TME), and the complexity of those microenvironments across cancer indications, within cancer indications and even within individual …

Next gen IO: what we thought we knew

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It’s mid-July and blazing hot here in Massachusetts. Luckily, we’re entering the summer vacation season and a break from the seemingly endless stream of biotech and oncology conferences that began in earnest last September, culminating in June with ASCO and EHA. We may also see a pause in the rush of biotech IPOs. There is always an interesting dynamic at play between progress as reported at medical conferences and the attractiveness of stock offerings – and this year the energy firing that dynamic is a bit unusual, especially across the immuno-oncology (IO) landscape.
As has been widely reported, ASCO was disappointing for next generation IO players. ‘Next generation’ refers to those companies developing assets that target diverse and novel immune regulatory targets, beyond anti-CTLA4 and anti-PD-(L)-1 antibodies. Essentially all companies bringing forward IPOs in the IO space have next-gen aspirations.
Why was ASCO disappointing? In part the answer is obvious: numerous expert reviews (eg. ours, from 2015: https://www.nature.com/articles/nrd4591) had promoted the compelling story that IO combinations would further improve the treatment of ever more patients in even more cancer indications. Such hypotheses drove intense investment in biotech companies, and the development of novel drugs targeting the diverse pathways of interest. During 2017 and 2018, IO combo hypotheses began reading out in clinical trial data, and the early results were underwhelming. This data wave culminated at ASCO in June.
The examples have by now been widely discussed: the collapse of the IDO inhibitor class with failures in late stage studies, the early defeat of an agonist anti-ICOS antibody, the realization that none of the many agonist antibodies to TNF superfamily receptors (4-1BB, OX40, GITR, CD27, etc.) were going to be quick wins, the modest activity of anti-CSF1R antibody, a miss from the VISTA program, and so on.
But the data were disappointing in a distinctly …

Angst in the IO Combo field – part 2 (lessons from #AACR17)

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I posed this question regarding IO combinations in the last post, leading up to AACR:
“Why the perception of angst then? The sentiment has been summed up as “everything will work a little, so what do we research/fund/advance? How do we choose? How will we differentiate”?
I was mulling over these questions as I prepared remarks for Jefferies Immuno-oncology conference – the slides below are taken from the deck I presented.
Even the comment “everything will work a little” now seems to be an overreach. We could instead say: “most combinations won’t work at all”, meaning they won’t work better than anti-PD-1/PD-L1 monotherapy or anti-CTLA4 monotherapy, or, that they won’t work better than those therapies used in combination with standard of care.
Remember two years ago? We were going to take an anti-PD-1 to “release the brake” and add anti-4-1BB or anti-OX40 to “step on the gas”. While it is still early, this seems to be an empty paradigm. Why? Certainly the 4-1BB and OX40 pathways are intensely potent when used to drive T cells directly (e.g. anti-CD3 + anti-4-1BB in vitro or as used in a CAR-T cell). Is it too early to tell? Have the wrong patients been enrolled in trials? Are the antibodies no good? Is it the Fc? IS THE TUMOR COLD?
So here we go, onto the next paradigm, summed up in the phrase “make cold tumors hot”. What happened to stepping on the gas?
At AACR, Dan Chen (from Genentech, a Roche company) laid out the case for using not 1, not 2, not 3, not 4, not 5 … but up to 11 different therapeutics to successfully treat a given tumor – he exaggerated to make the point that none of the current immune checkpoint inhibitors (ICIs) should be expected to work in synergy with anti-PD-1 therapy, a priori. Why …

Immuno-oncology (IO) combination therapy- why the angst?

Aleta Biotherapeutics, immuno-oncology, immunotherapy, PD-1, PD-L1

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Thoughts triggered by discussions over the last month or two, perceived sentiment on social media, reaction to clinical updates, and pre-AACR butterflies.
In 2015 Gordon Freeman of the Dana Farber Cancer Institute, one of the discoverers of the PD-1/PD-L1 axis, rang me up and asked if I would help write a review with he and Kathleen Mahoney, an oncologist doing a research rotation in his lab. We ambitiously laid out the argument that PD-1/PD-L1 directed therapeutics would be the backbone of important combination therapies and reviewed the classes of potential combinatorial checkpoints (http://www.nature.com/nrd/journal/v14/n8/full/nrd4591.html). We covered new immune checkpoint pathways within the Ig superfamily, T cell stimulatory receptors in the TNF receptor superfamily, stimulatory and inhibitory receptors on NK cells and macrophages, targets in the tumor microenvironment (TME), and so on. Importantly we also stopped to consider combinations with “traditional” cancer treatments, e.g. chemotherapy and radiation therapy, and also with “molecular” therapeutics, those directed to critical proteins that make cells cancerous. Regardless, it’s fair to say that we believed that pairing an anti-PD-1 mAb or an anti-PD-L1 mAb with another immuno-modulatory therapeutic would quickly yield impressive clinical results. A massive segment of the IO ecosystem (investors, oncologists, biopharma) shared this belief, and largely still does. Those stakeholders are betting clinical and R&D resources plus huge amounts of money on the promise of IO combinations. After all, the first IO combination of anti-CTLA4 mAb ipilimumab and anti-PD-1 mAb nivolumab has dramatically improved clinical response in advanced melanoma patients and to a lesser extent in advanced lung cancer patients. The downside is additive toxicity, and so the palpable feeling has been that new IO combinations would give a similar efficacy bump, perhaps even with less toxicity.
It’s now about two and a half years since we began drafting that paper and the inevitable letdown has …

CAR T updates – tangled tales unwound

ALL, B cell lymphoma, CAR T cells, Chimeric Antigen Receptor, CLL, immunotherapy, leukemia, lymphoblastic leukemia, lymphoma, Lymphomas, Leukemias, Myelomas, myeloma

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Last month we saw a biomedical media campaign go a bit off the rails. A press release from the American Association for the Advancement of Science (AAAS: see for example https://www.sciencenews.org/article/memory-cells-enhance-strategy-fighting-blood-cancers) and the Fred Hutchinson Cancer Center, was picked up by multiple media outlets who quickly spun the story of CAR-T-cell mediated rapid and complete clearance of B cell leukemias and some lymphomas from very ill patients and turned it into the “cancer cured” sort of headlines that serve as great click-bait but don’t do much to really educate the reader.

But what first caught my eye was an odd distortion of the data as presented in the session entitled “Fighting Cancer and Chronic Infections with T Cell Therapy: Promise and Progress” (see https://aaas.confex.com/aaas/2016/webprogram/Session12231.html). Several credible sources were telling very different stories about the progress presented. To take one example, BioWorld Today told the story of the clear benefit of using naive T cells as the recipient for cellular therapy, while FierceBiotech (and many other outlets) focused on the benefit of using memory T cells instead (see http://bit.ly/1UdLqDs). Indeed the claim was made that even a single memory T cell could affect a cure – which was not really the point, or an important conclusion of the presented works.

It follows that the pressers were used to talk up CAR T cell company stocks, which have been languishing along with the rest of biotech.

All of this came across as garbled and confusing. I found it all very frustrating.

So now I’ve gone through the abstracts presented at AAAS and some of the primary literature, and I’ve a Cliff Notes version of what data were actually presented and what the data mean and don’t mean. I seems clear that the confusion regarding the results arose from the oversimplified weaving of two talks (by Dirk Busch …

Some Adjacencies in Immuno-oncology

4-1BB, Aduro Biotech, Alligator Bioscience, Bellicum Pharmaceuticals, Biogen, BioNovion, Bristol Myers Squibb, cancer, CD27, CLDX, Coronado, CTLA4, Enumeral, Genentech, GITR, GITR Inc, HALO, Halozyme, immunology, immunotherapy, Innate Pharma, monoclonal antibodies, Novartis, oncology, OX40, PD-1, Pelican Therapeutics, Pfizer, Roche, Tekmira, TG Therapeutics, TNF receptors, tumor microenvironment

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Some thoughts to fill the space between AACR and ASCO (and the attendant frenzied biopharma/biotech IO deals).

Classical immune responses are composed of both innate and adaptive arms that coordinate to drive productive immunity, immunological expansion, persistence and resolution, and in some cases, immunological memory. The differences depend on the “quality” of the immune response, in the sense that the immunity is influenced by different cell types, cytokines, growth factors and other mediators, all of which utilize diverse intracellular signaling cascades to (usually) coordinate and control the immune response. Examples of dysregulated immune responses include autoimmunity, chronic inflammation, and ineffective immunity. The latter underlies the failure of the immune system to identify and destroy tumor cells.

Let’s look at an immune response as seen by an immunologist, in this case to a viral infection:
 

Of note are the wide variety of cell types involved, a requirement for MHC class I and II responses, the presence of antibodies, the potential role of the complement cascade, direct lysis by NK cells, and the potentially complex roles played by macrophages and other myeloid cells.

In the immune checkpoint field we have seen the impact of very specific signals on the ability of the T cell immune response to remain productive. Thus, the protein CTLA4 serves to blunt de novo responses to (in this case) tumor antigens, while the protein PD-1 serves to halt ongoing immune responses by restricting B cell expansion in the secondary lymphoid organs (spleen, lymph nodes and Peyer’s Patches) and by restricting T cell activity at the site of the immune response, thus, in the tumor itself. Approved and late stage drugs in the immune checkpoint space are those that target the CTLA4 and PD-1 pathways, as has been reviewed ad nauseum. Since CTLA4 and PD-1 block T cell-mediated immune responses at different stages it …