Category Archives: Aleta Biotherapeutics

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

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 the immuno-oncology drug development field.

These papers raised an interesting question – why are tertiary lymphoid structures (TLS) and by extension, secondary lymphoid organs such as lymph nodes, spleen, and Peyers patches, important for successful immune checkpoint blockade therapy (ICB)?  Aren’t we just waking up exhausted T cells, or moving T cells from the tumor margin into the tumor bed?  Isn’t that how anti-PD-1/anti-PD-L1 antibodies work?  Why should you need a TLS or lymph node?

These questions compel us to once again deconstruct the tumor and its surroundings.  One might start with the immediate tumor microenvironment (TME) under direct control by tumor cells, stroma and stroma-embedded fibroblasts and myeloid cells.  A second view might consider the vascularized tumor bed, with access to blood vessels and lymphatics.  A third view: the invasive tumor margin, where tumor cells are invading normal tissue.  A fourth: sites within the tumor where immune cells are present, either active or immobilized.  Fifth: associated lymphoid tissues and organs.  And so on, although it won’t help to make things too complicated.  Not by coincidence the list overlaps with the phases of the tumor-immunity cycle (Chen & Mellman, 2013).

 As to why you need a TLS or lymph node, the answer probably lies in the quality of the T cell pool.  As we learned from the work of many labs (reviewed here: https://doi.org/10.1038/s41577-019-0221-9) T cell exhaustion is a complex state, with subsets of cells having distinct functionality and fates.  Indeed, ‘exhaustion’ may be too broad a term.  For example, we know from Stephen Rosenberg’s work that TILs can be isolated from bulk tumor tissue, expanded using IL-2, and thereby “re-animated” ex vivo. Therefore, TILs are not always terminally exhausted.  Iovance has successfully exploited these findings and shown efficacy in late-stage clinical trials using patient-derived TILs to treat melanoma and cervical cancer.

These efforts can be traced back to the approval of high dose IL-2 for the treatment of renal cell carcinoma in 1992 and metastatic melanoma in 1998.  That 1992 date is notable, as IL-2 was discovered only 16 years earlier in Dr Robert Gallo’s lab (link).  Those approvals also are the basis of extensive efforts to produce less toxic variants of IL-2 by engineering selective IL-2 receptor engagement, as exemplified by the drug development work of Nektar, Alkermes, Roche and many others.  IL-2 is also used in the expansion of NK cells, indicating the pleiotropic activities of this cytokine.

Of note, TILs expanded in the presence of IL-2 can exhibit a differentiated phenotype that can shorten their long-term persistence and survival in vivo.  Recent analyses of successful TIL therapy have stressed the importance of a “stem-like” T cell population that has both proliferative and self-renewal capacity and fosters the development of long-lived memory T cells (Rosenberg lab: here).  I note in passing that their analyses suggest that strategies aimed at the CD39/CD73/A2AR pathway may have limited clinical impact.  A similar population of T cells has been associated with successful ICB therapy (discussed: link) and may play a role in productive CAR-T cell expansion.

A specific type of dendritic cell (DC) has been identified as a critical component of ICB therapy and this brings us back to lymph nodes and to TLS.  The cDC1 dendritic cell subset is implicated in the support of T cell mediated anti-tumor immunity (discussed by Gajewski & Cron here).  These are interesting cells that can be found in lymphoid organs, in inflamed tissues and within tumors.  Tumor antigens can make their way into lymphoid tissues by direct antigen drainage (review) with specific regions within lymph nodes supporting distinct DC populations and supporting distinct T cell responses (it turns out that B cells help with this spatial organization).  Tumor antigens can also be carried from the tumor into the lymph nodes by cDC1 themselves (link).  So now we have a narrative that accounts for the benefit of having lymphoid tissue in the context of anti-PD-1/PD-L1 therapy – this organized lymphoid tissue amplifies any existing anti-tumor response with a de novo response, sending additional T cell soldiers to the tumor front lines.

There are additional puzzles hidden within this narrative.  Possibly the one that bothers me the most is seeming failure of therapies that target T cell agonist pathways – notably 4-1BB and OX40 – to improve the response unleashed by ICB therapy.  Without burrowing deep into an immunology rabbit hole, I propose that anti-4-1BB and anti-OX40 agonist antibodies fail because they amplify signals in the wrong place or at the wrong time.  The immune system is tightly regulated and unkind to inappropriate signals.  Along these lines it is worth noting that completely blocking PD-1 will also backfire, as has been shown in disparate experimental systems (example).  This is translationally important, as PD-1-knockout CAR-T cells were eliminated in patients, either by active elimination or due to competitive disadvantage (paper, and presentation by Carl June, ASGCT 2020).  In contrast, signals that activate the DC compartment – GM-CSF, Flt3L and agonists that target CD40 (see Roche, Apexigen, Alligator, Seagen, Celldex and others) – do appear to augment anti-tumor immunity, and this may be the ideal way to think about boosting ICB therapies and perhaps CAR T cell therapies (hint).  A historical note: GM-CSF expression is a critical component of the T-VEC oncolytic viral therapy approved in 2015, just about 20 years after the first amino acid sequence data became available from the labs of Metcalf, Burgess, Dunn and colleagues during 1984-5 (here is a history by Glenn Dranoff).

Part 2: Knocking on other doors.

If location is critical, perhaps it’s time to move back to the TME.  I’ve thought for a long time that some TME-directed efforts are misguided.  I suspect several cell types commonly associated with the TME are epiphenomena that perhaps amplify, but do not create, the immunosuppressive microenvironment.  T-regulatory cells (T-regs) are one such cell type, and suppressive myeloid cells may be another.  The immuno-oncology drug development field has, to date, fallen short in attempts to deplete or alter these cell types for clinical benefit.

This should be surprising since T-regs and myeloid suppressor cells are abundant in TMEs across indications, but I would argue that tumor cells themselves and associated cell types in the tumor stroma, notably fibroblasts, are dominant.  ICB resistance signatures include VEGF, beta-catenin and TGF-beta – these factors appear to create the immunosuppressive milieu and subvert incoming immune cells.  Depleting T-regs or attempting to convert immunosuppressive myeloid cells (eg. ‘M2s’) to pro-inflammatory myeloid cells (eg. ‘M1s’) does not address the underlying immunosuppressive TME, which has arisen as a result of selective pressure on the tumor cell population.  I’ve discussed ICB resistance previously (see here and here).

However, the immunosuppressive TME and its attendant cell types can be upended, most notably by triggering evolutionarily ancient pathways that trump the immunosuppressive signals.  Many of these pathways are well known – the TLR7/8 and TLR9 agonists, the STING agonists, and the CD47 pathway inhibitors being prosecuted by many companies (see eg. AstraZeneca’s MEDI9197, a TLR7/8 agonist, Glaxo’s GSK3745417 STING agonist, I-Mab’s CD47 program, among many others).  Of note, localization of agonist signaling is critical in this space as well.  For example, TLR signaling is generally targeted at tumor cells directly, whereas it is debated whether STING agonists should target myeloid-lineage cells within the TME, tumor cells themselves, or both.

I particularly like the idea of engineering CD47 antagonism into other modalities, eg. T cell engagers.  Indeed, blocking CD47 to induce myeloid cell phagocytic activity is an active field, and this has encouraged a search for similar signals, for example, the Siglec10/CD24 pathway.  Moving even further afield we encounter quite novel myeloid cell signals and can consider pathways that are not as widely targeted.  One is the ILT (aka LILBR) system, where most activity is centered on antibodies to ILT2 and ILT4.  Here we begin to intersect with multiple cell types, as ILT2 is expressed by monocytes, macrophages, DC, B cells, and subsets of T cells and NK cells, and ILT4 is expressed by neutrophils, myeloid cells and DCs. These proteins have inhibitory signaling domains that are triggered by MHC binding, including to the HLA-G protein, normally expressed on myeloid lineage antigen-presenting cells (macrophages, DCs) where expression serves to immune-suppress interacting cells.  HLA-G is also overexpressed on many tumor cell types.  Thus, the ILT/HLA-G system appears to be another immune checkpoint, perhaps with a broader range of activity than the PD-1 system.  Merck has shown early positive clinical data using an antagonist anti-ILT4 antibody, MK-4830 (from Agenus), in combination with pembrolizumab (anti-PD-1) in heavily pretreated cancer patients (presented at ESMO 2020).  Jounce Therapeutics and Immune-Onc showed preclinical data at SITC 2020 on their anti-LILBR2 (ILT-4) programs, and there are additional efforts underway.  I suspect this field will grow quickly, and perhaps match the TIGIT/DNAM-1 space in interest and complexity.

Part 3. Fc-hacking immune responses.

As mentioned above, the immune system has strict rules and regulations, and can be resistant to having these over-ridden by therapeutics.  Hacks are possible of course, as shown by the success of CAR-T cells and the T-cell engager bispecifics.  Along these lines, decades of work on the Fc-domains of antibodies has allowed fine tuning of biologic therapies.  We are all familiar with optimization of ADCC and CDC activity (up or down), but more recent advances are less widely known.  I want to explore two examples – one will bring us back to LN and cDC1 activation, the other will advance the discussion on myeloid cell activation and will introduce the interaction of myeloid cells and neutrophils as a novel component of the anti-cancer immune response.

Jeffrey Ravitch’s lab recently published a method for Fc engineering of IgG antibodies for selective high-affinity binding to the activating Fcγ receptor FcγRIIa (paper).  In a viral respiratory model (in mice having human FcγRs) this Fc-hack resulted in an enhanced ability to prevent or treat lethal viral respiratory infection, with increased maturation of dendritic cells and the induction of anti-viral CD8+ T cell responses. Specifically, they noted up-regulation of CD40 expression in the cDC1 subset—the dendritic cell population specialized for cross-presentation and CD8 T cell stimulation in the lung virus model, and the very same DC subset we discussed earlier in the context of TLS and LN-mediated anti-tumor responses.  Just to close the circle, Fumito Ito and colleagues used irradiation, Flt3L, TLR and CD40 stimulation to demonstrate cDC1 induction of stem-cell line CD8+ T cells in a variety of murine tumor models (linked here).  It follows that engineering antibodies with the selectivity demonstrated in the Ravetch paper will find utility in the anti-tumor field.

I started off by referencing presentations from Ron Germain and Michael Dustin at SITC 2019, over a year ago.  Dr Germain presented a story that really struck a chord for me (see Uderhardt et al. 2019).  In tissue injury and pathogen infection models, neutrophils comprise the first line of defense, as innate immune signals cause them to swarm at the affected site. Early infiltrating neutrophils undergo activation induced cell death, which can drastically amplify the response and potentially cause tissue damage. In order to terminate this potent immune response tissue-resident macrophages rapidly sense neutrophil activity and cell death and extend membrane processes to limit the damage.  This ‘‘cloaking’’ mechanism thus limits neutrophil activation.  Of note, neutrophils can be abundant in tumors where they have been linked to diverse activities ranging from potent anti-tumor immunity to immune-suppression.  Neutrophils, like myeloid cells and NK cells, can be hacked using Fc-receptor engagement.  Neutrophils express FcγRIIA, just discussed in the context of cDC1 activation, and therefore it will be interesting to examine the activation of these (and other the FcγRIIA-expressing cells) in the context of IgG Fc-engineering.  Neutrophils and myeloid cells also express FcαRI, a very interesting receptor that when engaged by IgA-isotype antibodies triggers targeted cell killing.  Neutrophils will engage in phagocytosis, degranulation and reactive oxygen production to mediate killing after FcαRI engagement, while myeloid cells will be triggered to engulf targeted cells. The specific responses induced depend on the valency of IgA (monomeric, dimeric, aggregated) but it seems likely that the Fc-domain can be hacked in order to optimize productive engagement.  With a recent spotlight shown on IgM as an Fc-engaging platform (see IgM Biosciences) we can anticipate accelerated drug development across all of these diverse Ig-classes.

To wrap up – as we move forward in the related disciplines of immuno-oncology and cell therapy, we should consider these principles:  optimizing T cell/DC interactions, localizing immune checkpoint therapy to lymphoid tissues, and engaging additional cells to bring the full power of the immune system to the anti-tumor battle.

Stay tuned.

Updates from #CowenHealthCare 2020 – CAR T and it’s competitors

If you work in cell therapy you have follow all kinds of therapeutic developments in indications of interest which for us at Aleta Biotherapeutics (www.aletabio.com) includes specific solid tumor indications, and several hematologic malignancies.

Over the last few days we’ve gotten interesting updates regarding diverse hematologic malignancies, including news about therapeutics for front line (newly treated) or relapsed or refractory (r/r) Non-Hodgkin Lymphoma (NHL), multiple myeloma (MM) and acute myeloid leukemia (AML) patients and the myelodysplastic syndromes (MDS). Note here that the reference to different lines of therapy – front line or early line vs r/r, because the treatment paradigms change as patients fail earlier lines of therapy, ie. as they become refractory to or relapse from their current therapy. This can become a long and arduous battle for patients who repeatedly fail treatment. Unfortunately, this is often the case in r/r MM, r/r AML and MDS and in some subtypes of r/r NHL.

On Monday (2 March 2020) I attended the “Cell Therapy & Myeloma” panel at the 40th Annual Cowen Heath Care Conference. This panel covered much more than the title implies, and I really liked the format which is built on the back of questions posed to the audience, to an (unnamed) group of specialists in the field who were polled in advance, and to the seated key opinion leaders (KOLs), in this case Dr Deepu Madduri (Mt Sinai) and Dr Jacob Soumerai (MGH).

They covered a lot of ground.

The first series of questions sought to pin down trends in r/r Follicular lymphoma (FL) a subtype of NHL that can become difficult to treat if patients fail successive lines of treatment. The Leukemia Lymphoma Society has a primer here -https://lymphoma.org/aboutlymphoma/nhl/fl/relapsedfl/.  There has been brisk drug development in r/r NHL including FL. Novel drug classes include CAR-CD19 T cells, bispecific T cell engagers, small molecule drugs (targeting PI3K, Bcl2, BTK, EZH2) and new antibodies. The Cowen panel worked through a series of questions regarding this landscape and there were several key takeaways.

One was the clear preference, by the anonymously polled specialists and by the seated panelists, for CAR-CD19 therapy as the most exciting new drug for r/r FL. The driver here is the durability of response (DOR) in really late line patients and the sense that both overall response rate (ORR) and DOR will only improve as these cell therapeutics move to earlier lines of therapy. It was striking that several classes of bispecific antibodies (the CD3 x CD20 and CD3 x CD19 bispecifics) elicited strong enthusiasm from the audience (mostly analysts and investors) but only muted enthusiasm from the KOLs. This lack of enthusiasm had 2 distinct bases: 1) limited data to date, and 2) “I can give a bispecific after I give a CAR T, but not the other way around”, which was a very interesting thought (and given despite of the few case reports of CD3 x CD20 bispecific therapy working in several relapsed CAR-T patients). I think that in later line patients these clinicians want to keep their options open as long as possible.

Among the other classes of therapeutics, Epizyme’s EZH2 inhibitor tazemetostat received significant support based on the ability to select EZH2-mutated patients, and on good DOR and on good tolerability, the latter thought to be better than the PI3Kdelta class inhibitors, BTK inhibitors or BCl2 inhibition. The consensus was that tazemetostat could see up to 20% market penetration in third line FL after the expected launch in June 2020.

Among the PI3Kdelta inhibitors, Bayer’s copanlisib was singled out as best-in-class with little differentiation among the others (from Gilead, Verastem, MEI, Incyte, or TG Therapeutics). Finally, in this setting of r/r FL, both venetoclax (a Bcl2-inhibitor) and polatuzumab vedotin (a CD79b antibody-drug conjugate), were relegated to minor use by the specialists and panelists.

The uptake of CAR-CD19 therapies has been brisk, and the panelists highlighted quicker payor approvals and the accelerating pace of referrals to cell therapy centers. The consensus is for 30% increase in patient number treated in 2020 (so roughly 1350 patients in the US, vs 1050 treated last year).

The discussion stayed on CAR-CD19 therapeutics to touch on some of the newer trials and entrants. Kite/Gilead is running a Phase III trial of axi-cel (axicabtagene ciloleucel, brand name Yescarta) in second line DLBCL patients vs a standard of care regimen of high dose chemotherapy followed by an autologous stem cell transplant. Data are anticipated in the second half of 2020. The Cowen moderators passed the question: will this trial show a progression free survival (PSF) benefit?  Mind you, this is a low bar since overall survival – the shining triumph of cell therapy – is not part of the question. The audience (again, mainly investors and analysts) was overwhelming positive, giving about 70% odds of a positive impact on PFS. Here the panelists agreed, citing the fact that this trial was enrolling high-risk patients and therefore the comparator arm of the trial (chemo + ASCT) should do very poorly. Success with this trial would move axi-cel up a line of therapy (from 3rd or later to 2nd or later) and bolster the health care value argument that patients may avoid ASCT altogether.  We are apparently already seeing this effect, as a talk at #TCMT20 highlighted the steep decline in transplants being done in DLBCL.

Sticking with axi-cel, this CAR-CD19 cell therapy was highlighted as the one most likely to be the market leader by 2023, based on the (currently) much shorter manufacturing and turnaround time as compared to tisa-cel (tisagenlecleucel from Novartis, brand name Kymriah). The panelists agreed with the specialist poll, despite the fact that they also felt that tisa-cel may be better tolerated by patients overall. Further, the panelists did note that the difference in manufacturing turnaround was likely to diminish as Novartis improves its product workflow. So we’ll have to wait and see.

Competition may also play a role.  The long-awaited Juno > Celgene > BristolMyers Squibb CAR-CD19 liso-cel (lisocabtagene maraleucel) should see its first approval soon, and several allogeneic and non-T cell based programs are advancing. Cowen’s moderators highlighted a number of these for discussion. Allogene CAR-CD19, called ALLO-501 is currently in a Phase 1 trial enrolling r/r diffuse large B cell lymphoma (DLBCL) and r/r FL patients, with initial data expected later this year. The moderators put forward the question: what percent of (responding) patients have to show a durable response for this to be an exciting option to the autologous CAR-CD19 products. It’s a complex question since the current approved CAR-CD19s show about a 50% durable response rate within the responders, where a goodly proportion of the patients that do not have a durable response are relapsing after a response, sometimes with CD19-negative lymphoma or leukemia (ie. the cancer has undergone natural selection and loses target antigen expression). The polled specialists and the panelists wanted to see a pretty high durable response rate, 35-40% (specialists) up to 50% (the panelists). If the field were to see responses as good as axi-cel, tisa-cel and liso-cel, this would be “a huge advance”, according to Dr Soumerai of MGH.

Of note, Allogene itself was a bit more cautious at their public company presentation later in the day. Dr David Chang, Allogene’s CEO, provided some guidance and set expectations. He noted that the company would report early data form the ALLO-501 program at #ASCO20 and/or #EHA20 but stressed the readouts of safety and degree of lymphodepletion from up to 3 dose cohorts, and with several different doses of their lymphodepletion agent ALLO-647, and anti-CD52 antibody. In the ALLO-501 trial this is given along with the lymphodepeleting chemotherapy combination of cyclophosphamide and fludarabine (Cy-Flu). Among the other allogeneic and off-the-shelf CAR-CD19 programs several were highlighted either by the audience (Fate Therapeutics induced CAR-NKs) or the panelists (the Takeda/MD Anderson NK program). Other programs from Atara, CRISPR, and Precision all would have to show some or more data in order to get the specialists or the panelists to take notice.

Notably, there was consensus among the audience, polled specialists and panelists that CD3 x CD20 bispecifics would be less efficacious than CAR T cells, regardless of the specific therapeutics (eg. from Roche or Regeneron or Genmab). Further, Dr Madduri expressed concern at the need to keep dosing patients both because of inconvenience and possible safety over time. Her view is that patients prefer a single dose CAR.

Finally in the r/r DLBCL space, both polled specialists and the panelists saw minimal roles for the anti-CD79b-drug conjugate polatuzumab vedotin (brand name Polivy, from Roche) or the anti-CD19-ADCC competent antibody tafasitamab (from Morphosys, which now has a 30 August PDUFA date with FDA).  Both of these biologics need to be given in combination with other therapeutics and there did not appear to be a benefit over standard combinations. More specifically, polatuzumab vedotin is given with rituximab and bendamustine and was considered “tolerable” but perhaps best used in a bridge to transplantation setting or a bridge to CAR-CD19 cell therapy. Tafasitamab was recently written up by Jabob Plieth here: https://www.evaluate.com/vantage/articles/analysis/why-2020-spotlight-will-fall-tafasitamab.

Turning to r/r MM there were a series of questions about lines of therapy and which were preferred. For newly diagnosed patients and for second-line patients the clearly favored standard of care was an ‘ImID’ (immunomodulatory agent, eg. revlimid) plus the anti-CD38 antibody daratumumab (brand name Darzalex, from Johnson & Johnson’s Janssen division) plus dexamethasone (aka triple therapy) with perhaps a proteasome inhibitor added (thus, a quad). The use of daratumumab in early line therapy will continue to grow as it is payor-approved for early-line use.

For later line therapy, the moderators first brought up selinexor (brand name Xpovio, from Karyopharm Therapeutics), a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE), which was granted accelerated approval last year for use in in combination with dexamethasone for adult r/r MM patients who received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two ImIDs, and an anti-CD38 monoclonal antibody. There was a consensus view that this drug will see flat to diminishing use due to poor tolerability. Dr Madduri noted that she gives this drug once week rather than twice a day (as labeled) in an effort to improve patient tolerance and only used it as a bridge to clinical trial enrollment (ie. on something else, for example, CAR-BCMA cellular therapy. Curiously there were no questions about isatuximab-irfc (brand name Sarclisa, from Sanofi-Aventis), newly approved in combination with pomalidomide and dexamethasone for adult patients with r/r/ MM and at least two prior therapies (see this SITC writeup: https://www.sitcancer.org/aboutsitc/press-releases/2020/isatuximab-irfc).

As for CAR T cells for multiple myeloma, the panelists were hesitant to pick a winner between the two advanced CAR-BCMA programs: bb2121 (Bluebird) and JNJ-4528 (from J&J, formally called LCAR-B38M) until J&J updated PFS data. At their public company presentation Nick Leschly, Bluebird’s CEO, noted that they will file the BLA for bb2121 (now called idecabtagene vicleucel or ide-cel) in the first half of this year, and would release longer-term follow-up data from the ide-cel clinical trials KarMMa and CRB-401 in the second half of the year. The BLA will be filed despite the “slow-down” from FDA necessitated by the agency’s request for additional lentivirus production characterization information from their chosen cell suspension manufacturing method (no details given). What the FDA has asked for apparently is both different from and more than the EU agency (EMA) wanted.

On the allogeneic CAR T cell front, Dr Chang at Allogene noted that they would have early data on ALLO-715 (their version of a CAR-BCMA therapy) at #ASH20. Here he noted they are considering dropping the Cy-Flu lymphodepletion and just using their anti-CD52 antibody to lymphodeplete, we’ll see (this doesn’t strike me as realistic).

In general both the polled specialists and the panelists were more enthusiastic about CAR-BCMA therapy than several other modalities, including belantamab mafodotin (from GSK), an antibody-drug conjugate, composed of an anti-BCMA monoclonal antibody bound to auristatin F. This drug was thought to be not quite good enough given the unmet need, there remain concerns about the ocular toxicity (the bane of ADC technology) and keen disappointment that the response rate dropped below 30% ORR in daratumumab-refractory patients. Clearly this therapeutic will see some use in late line therapy, and further clinical development has yielded results in earlier line as reported on 2 March (see https://www.evaluate.com/vantage/articles/news/trial-results/karyopharm-comes-boston-springtime). A similar wait-and-see approach is being taken by these specialists and panelists to the CD3 x BCMA bispecifics, which are currently viewed as best for community hospital settings without CAR T cell capacity or for patients who cannot wait for the cell therapy production.

One theme in r/r MM is the concern that patients are still not being cured, even with cell therapies. The gradual relapse from CAR-BCMA treatment that one sees in all the clinical studies has been linked either to CAR T persistence being limited or to diminished BCMA antigen expression on the cancer cells. Of course, these two things may be related. One desire expressed by Dr Madduri was for a CAR-BCMA therapy with better persistence properties.

Two short notes while we’re here. Gilead stated at their public company presentation during Cowen Health Care that the value driver for the Forty Seven acquisition was the MDS data (https://xconomy.com/san-francisco/2020/03/02/gilead-boosts-cancer-drug-pipeline-with-4-9b-deal-for-forty-seven/). And hematologic drug heavyweight venetoclax (the Bcl-2 inhibitor from Abbvie) scored a miss in an AML confirmatory trial (https//pharmaphorum.com/news/abbvie-roches-venclexta-fails-in-confirmatory-aml-trial/). In summary, a busy couple of days.

As many readers know, Aleta Biotherapeutics builds cellular therapeutics with exemplary persistence and fitness properties. We have two cell therapy programs heading for the clinic now. One will treat r/r AML patients both in the pediatric and adult patient populations. Our solid tumor program is designed to treat patients relapsing from breast or lung cancer with brain metastases. We also have a biologics program specifically created to ‘rescue’ CAR-CD19 T cells in patients relapsing from therapy. You can find out more at www.aletabio.com or email me at paul.rennert@aletabio.com or just call me at 1-508-282-6370 and of course follow me on Twitter @PDRennert and @BioAleta.

That’s it for now.  Stay tuned.

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

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 set in. What happened? Let’s cover a few issues:

- Several marque IO combinations have been disappointing so far. Last year we saw unimpressive results from urelumab (anti-4-1BB) in combination with nivolumab (anti-PD-1) and of epacadostat (an IDO inhibitor) paired with pembrolizumab (anti-PD-1).

- Monotherapy trials of therapeutics directed to hot new targets (OX40, CSF1R, A2AR etc.) did not produce any dramatic results, forcing a reevaluation of the potential for truly transformative clinical synergy in the IO combination setting.

- These first two points also reminded the field of how limited preclinical mouse modeling can be.

- Combinations of standard of care with anti-CTLA4 mAb ipilimumab and with PD-1 pathway inhibitors have begun to show promising results, raising the efficacy bar in a variety of indications. There have been several startling examples: the combination of pembrolizumab plus chemotherapy in first line lung cancer, which doubled response rates over pembrolizumab alone; the combination of cobimetinib (a MEK inhibitor) with atezolizumab (anti-PD-L1 mAb) in colorectal cancer (MSS-type) which produced clinical responses in patient population generally non-responsive to anti-PD-1 pathway inhibition; the combination of atezolizumab plus bevacizumab (anti-VEGF) in renal cell carcinoma, showing promising early results; and so on.

- We can add the realization that relapses are a growing issue in the field, with approximately 30% of anti-CTLA4 or anti-PD-1 pathway treated patients eventually losing the anti-tumor response.

Note here that all of this is happening in a rapidly evolving landscape and is subject to snap-judgment reevaluation as clinical data continue to come in. For example, rumors that IDO inhibition is working well have been spreading in advance of the upcoming AACR conference. Indeed the clinical work on all of the immuno-modulatory pathways and IO combinations has increased, and the race to improve care in diverse indications continues. There will be additional success stories.

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”? Such sentiment puts intense pressure on discovery, preclinical and early clinical programs to show robust benefit or, and perhaps this is easier, benefit in particular indications or clinical settings. I started thinking about this recently when a friend of mine walked me through a very pretty early stage program targeting a novel pathway. It was really quite impressive but it was also apparent that the hurdles the program would have to clear were considerable. Indeed it seemed likely that validation of the therapeutic hypothesis (that this particular inhibitor would be useful in IO) would not come from preclinical data in mice (no matter how pretty), nor from a Phase 1 dose escalation safety study, nor from a Phase 1 expansion cohort, but would require Phase 2 data from a combination study with an anti-PD-1 pathway therapeutic. That is, 5+ years from now, assuming all went smoothly. To advance such a therapeutic will take intense focus in order to build a fundable narrative, and will require stringent stage-gates along the way. Even then it will be very hard to pull it off. If this reminds you of the “valley of death” we used to talk about in the biotech realm, well, it should.

What should we look for to shake up this landscape? As mentioned, this is a rapidly evolving space. We have already seen a shift in language (“step on the gas” vs. “make a cold tumor hot” is one good example), but let’s list a few:

- “Cold tumors” have no immune response to stimulate. Making them “hot” is a hot field that includes oncolytic virus therapeutics, vaccines, “danger signals” (TLRs, STING, etc), and, to loop back around, chemotherapy and radiation therapy.

- Relapsed patients – as noted above we are seeing ~30% relapse rate in immunotherapy treated patients. Understanding the basis for relapse is a promising field and one that an emerging therapeutic could (and very likely will) productively target.

- Targeting the TME in cold tumors and in unresponsive tumors (the difference is the unresponsive tumors look like they should respond, in that they contain T cells). This is a vast field that covers tumor cell and stromal cell targets, secreted factors, tumor and T cell metabolism and on and on. One can imagine a setting in which a particular TME is characterized (by IHC, Txp or other means) and the appropriate immuno-modulatory therapeutics are applied. We see this paradigm emerging in some indications already. This would certainly be useful as a personalized medicine approach and could be an excellent way to position an emerging therapeutic.

We could go further to talk about the neoantigen composition of particular tumor types, the role of the underlying mutanome, the plasticity of the TME (it’s a chameleon), metabolic checkpoints, and other, potentially novel, targets.

All of this is under intense and active investigation and important data will emerge in time. Until then, nascent immunotherapy programs need to tell a clear and compelling story in order to attract the interest of investors, biopharma and ultimately, oncology clinical trialists. Those that fail to develop a compelling narrative are likely to struggle.

I’ll just end on a few narratives I really like for IO combinations going forward:

- the role of innate immunity in activating immune responses and expanding existing responses (e.g. immune primers like STING agonists and NK cell activators like lirilumab)

- the role of adenosine in maintaining an immunosuppressed (ie. non-responsive) TME (thus inhibitors of A2AR, CD39, CD73)

- the role of beta-catenin signaling in non-responsive tumors (while carefully selecting the mode of inhibition)

- the role of TGF-beta activity in resistance to PD-1 pathway therapeutics (again, with care in selecting the mode of inhibition)

of course at Aleta we’ve charted a different course, ever mindful of the need to focus where we see clear yet tractable unmet need. so we’ll see, starting with AACR in early April, kicking off an active medical conference season.

stay tuned.