sep 02, 2015 biotechnology - noble capital...

Sep 02, 2015

BiotechnologyThe Brave New World of Cancer Immunotherapy

Success in cancer immunotherapy is built on decades of diligent research and development; learning from past failures and incremental successes, a new direction has been catalyzed; in cancer immunotherapy, we may have failed forward towards success

A new and nuanced understanding of the interaction between tumors and the host immune response and the complexities in the tumor microenvironment has been critical in immunotherapy drug development

Reversing the immune-suppression that tumors exert, as opposed to exclusively targeting immune stimulatory pathways or mutated signaling pathways or the cytotoxic destruction of tumors, has been the difference (with immune checkpoint inhibitors)

The conquest of cancer needs immunotherapy; besides the tumor-inflicted immune-suppression, aspects of tumor biology such as heterogeneity & genetic plasticity of tumors limit the efficacy of conventional therapies (chemotherapy, kinase inhibitors)

The new armory of immunotherapy consists of approved and emerging immune checkpoint inhibitors, co-stimulators, engineered antibodies - bispecific antibodies, CAR T cells, CAR NK cells amongst others; combination approaches will drive future advances

Equity ResearchRahul Jasuja, PhD, Managing Director, Biotechnology Research (561) 912-1736 [email protected]

Noble Life Science PartnersTrading: (561) 998-5489 Sales: (561) 998-5491 www.noblelsp.com

Refer to the last two pages of this report for Disclosures

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The Brave New World of Cancer Immunotherapy

On the surface it may seem that the progress in immunotherapy of cancer has predominantly occurred in the last few years. It is true that the most significant regulatory approvals, immune checkpoint inhibitors, came in the last year and the first checkpoint inhibitor was approved in 2011. However, success in cancer immunotherapy is built on decades of diligent and innovative research and development, and numerous academic and corporate clinical trial failures. Past failures and the step by step incremental successes, so typical of biomedical research, have now catalyzed a new direction. In cancer immunotherapy drug development, we may have failed forward towards success.

The regulatory approvals of Bristol-Myers Squibb's (BMY) Yervoy (ipilimumab, CTLA-4 inhibitor) in March 2011 and Opdivo (nivolumab, PD-1 inhibitor) in December 2014; and Merck's (MRK) Keytruda (pembrolizumab, PD-1 inhibitor) in September 2014 are pioneering immune checkpoint inhibitor based immunotherapies that have meaningfully changed metastatic melanoma treatment. Opdiva has since been approved for advanced squamous non-small cell lung cancer, and Keytruda may follow soon. Potentially, this may be just the tip of the iceberg. The developing immunotherapy pipeline looks robust, with novel approaches such as Chimeric Antigen Receptor (CAR) T cells, novel checkpoint inhibitors, cytokine modulators, novel T cell co-stimulators, and bi-specific/tri-specific antibodies amongst other approaches. Recently, a bi-specific antibody developed by Amgen (AMGN) (Blincyto, blinatumomab) that targets CD19 on B-cells and CD3 on T cells was approved for acute lymphocytic leukemia (ALL). Furthermore, the prospect of enhancing tumor response rates with patient-specific predictive biomarkers, combination approaches with different immunotherapy agents as well as combination with conventional treatment regimens (radiation, chemotherapy, and signaling pathway inhibitors) is welcome news for patients, clinicians, and all stakeholders in the oncology community.

A new and nuanced understanding of the interaction between tumors and the host immune response and the complexities in the tumor microenvironment has been critical in immunotherapy drug development. Reversing the immune-suppression that tumors exert on the host immune system, as opposed to exclusively targeting immune stimulatory pathways or mutated signaling pathways or the cytotoxic destruction of tumors, has been the difference (with immune checkpoint inhibitors). However, response rates still need to improve and complementary combination approaches to checkpoint inhibitors may be the next advance. Combination approaches with immune checkpoint inhibitors are in development with T cell co-stimulators (OX40, CD27, 41BB, GITR, TNFRSF25), with engineered Listeria monocytogenes immunotherapy, with local delivery of immunomodulatory cytokines such as IL-12 and a host of other combinations. Novel immune checkpoint inhibitors targeting Indoleamine (2,3)-dioxygenase (IDO), phosphatidylserine and CD47 on macrophages are in development as well and could be studied in combination with PD-1. In addition, the next generation of improved CAR-T cell and novel innate immunity targeting CAR-NK cell technologies are in the pipeline. CAR-NK cells harness the potential of Natural Killer cells (NK cells). NK-cells, unlike T cells, are not antigen restricted and have the added virtue of connecting innate with adaptive immunity.

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Biotechnology | 09/02/2015Rahul Jasuja, PhD [email protected] (561) 912-1736

Strong interest by Big Pharma and the investor community in immunotherapy this time around is a reflection of a deeper understanding of tumor biology, the mechanisms underlying tumor evasion of the immune system, understanding molecular heterogeneity within tumors, selection of the right patient population and last, but not the least, parallel innovation in molecular biology techniques and research & development tools such as next generation sequencing, single cell analysis, bioinformatics amongst others.

Besides interest by Big Pharma, successful IPOs and follow-on financings for Juno (JUNO), Adaptimmune (ADAP), Kite (KITE), Affimed (AFMD), Bluebird (BLUE), Bellicum (BLCM), Aduro (ADRO) and NantKwest (NK) amongst others, shows prolonged investor appetite for immunotherapy at emerging biotechnology companies. Notable is the biggest biotech IPO in at least the last decade, NantKwest (formerly Conkwest) that reached $2.6B in market capitalization on its public markets debut. NantKwest (NK) develops off the shelf NK cell based immunotherapies.

The conquest of cancer needs immunotherapy

"If we are ever going to use the word 'cure', the immune system is going to have to come into play"Stephen Hodi, director of the melanoma center at Dana-Farber Cancer Institute in Boston.

"Why would cancer devote so much energy to avoid the immune system if the immune system didn't have the potential to reject the cancer?" Robert Vonderheide from the Abramson Cancer Center of the University of Pennsylvania

Tumors evade or modulate the host immune response in several ways to ensure survival and propagation. Evasion strategies include modifications of immune cell metabolism, modulation of T cell, myeloid derived suppressor cells, NK cell and macrophage signaling amongst other changes that result in inhibitory cytokine release. This leads to an immune-suppressive milieu in the tumor microenvironment that supports tumor progression.

Given the nature of tumor-host interaction, in order to eradicate the tumor, the immune system must come into play. For example, chemotherapy and radiation may kill most cells in the tumor; however, cancer stem cells may remain intact, resulting in resistance to therapy. This ‘stemness' i.e. the ability of cancer stem cells to self-renew and differentiate, can give rise to heterogeneous lineages of resistant cancer cells. Fundamental aspects of tumor biology listed below, limit conventional approaches i.e. cytotoxic (chemotherapy, radiation), immune stimulatory approaches (IL-2, cancer vaccines), and targeted therapies (kinase inhibitors) from being effective:

Heterogeneity and genetic plasticity of cancer cells

Immunosuppressive tumor microenvironment – cytotoxic, immune stimulatory and targeted therapies do not

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reverse immune-suppression

Cancer stem cells can renew the cancer (as discussed above)

Cancer cells are of host origin – most therapeutic interventions have a limited therapeutic window before toxicity and tolerability issues manifest

Reversing the tumor-inflicted immune-suppression

The current success in cancer immunotherapy drug development has been helped by a new and nuanced understanding of the interaction between tumors and the host immune response and the complexities in the tumor microenvironment. In general, past approaches in cancer immunotherapy were directed at stimulating the immune response without reversing the tumor inflicted immuno-suppression (i.e. stepping on the accelerator without releasing the brake). Tumors harness immune checkpoint pathways (example PD-1/PD-L1 and CTLA-4) that are negative regulators of the immune system to suppress an anti-tumor response, benefiting tumor growth. Pharmacological inhibition of these immune checkpoint pathways can lead to re-activation of the immune system and an anti-tumor response. This notion relates to the concept discussed above that tumors expend much energy to neutralize the immune response in order to survive, and interrupting these pathways can restore the immune response.

Exhibit 1: Reversing the tumor-inflicted immune suppression with checkpoint blockade restores the balance so that immuno-stimulatory mechanisms come into play.

Reference: Adachi K & Tamada K; Cancer Sci (2015) May 15.

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The vast majority of success in cancer immunotherapy has been driven by immune-modulating antibodies targeting pivotal checkpoints (CTLA-4 and PD-1/PD-L1). In addition, other immune-modulating molecules targeting inhibitory or stimulatory pathways are being developed. Future progress will be driven by combination studies with checkpoint inhibitors that improve tumor responses and patient survival beyond that achieved by checkpoint inhibitors alone.

The promise of improved survival and durable tumor responses

Over the last two decades, the shift has taken place from harsh cytotoxic agents and cell cycle inhibitors that treat cancer without specificity to targeted approaches based on an improved understanding of the molecular mechanisms underlying cancer biology. Conventional or "old" immunotherapy (i.e. those that did not reverse the immune-suppression) such as immune stimulatory approaches using systemic IL-2, IL-12, and cancer vaccines have had modest success given toxicity and/or limited efficacy in a small number of patients (5 to 10%). Targeted approaches block oncogenic pathways that drive the tumor - includes kinase inhibitors or antibodies against tumor growth receptors or over-expressed tumor antigens. Resistance to targeted oncology therapy approaches is inevitable, as tumors adapt and lean on alternative pro-survival pathways. In contrast, restoring immune competence by breaking tolerance to the tumor with immunotherapy, results in a robust and broad productive anti-tumor response. Restoring immune competence drives an anti-tumor response that can harnesses innate and adaptive mechanisms including a memory CD8 T cell response to eradicate the tumor. For this reason targeted oncology therapy approaches may induce a rapid tumor response initially, but most are not durable. Recent cancer immunotherapy approaches followed the incremental progress made by targeted oncology and made a meaningful change as depicted in Exhibit 2, leading to durable tumor responses and improved survival.

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Exhibit 2: Effects of immunotherapy and targeted therapy on survival curves. Generally, immunotherapy induces a relatively low percentage, but highly durable tumor response. Targeted therapies such as kinase inhibitors block oncogenes that drive the tumor, inducing a rapid tumor response but most are not durable. With targeted therapies, early improvement is observed, but not necessarily leading to improved survival. The blue line denotes either immunotherapy or targeted therapy compared to conventional chemotherapy/radiation therapy denoted in red.

Reference: Ribas A et al; Clin Cancer Res. 2012 Jan 15;18(2):336-41

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Combination approaches: the next phase of cancer immunotherapy progress

Checkpoint inhibitors have made a marked difference in the treatment of cancer, increasing patient overall survival in difficult to treat tumors – metastatic melanoma and advanced non small cell lung cancer so far. However, only about 20-40% of patients respond to checkpoint inhibitor therapy. While these response rates are a significant improvement in metastatic disease over standard of care, there is room for immense improvement as we begin to harness the power of immunotherapy with new strategies. To increase tumor response rates and patient survival beyond that achieved with current checkpoint inhibitors, combination approaches are the next step. Checkpoint inhibitors may be effective in immunogenic tumors with high tumor infiltrating lymphocytes (TILs), where TILs are immune-suppressed. For tumors with low TILs, innate & adaptive immunity needs to be harnessed for a broad T cell effector response. To improve tumor responses, immunotherapy approaches beyond breaking tolerance to tumor antigens (i.e. checkpoint inhibition) are

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needed. Such approaches should subsequently activate the effector/tumor killing arm of adaptive and innate immunity.

Exhibit 3: Can combination therapy shift the survival curves further? A hypothetical depiction below shows potential of combination approaches in increasing survival rates.

Reference: Clin Cancer Res 2013;19: 5300-5309; Citi, 14 February 2014, Immunotherapy - The Beginning of the End for Cancer

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Can combination approaches tackle PD-1/PD-L1 refractory tumors?

Arguably, PD-1/PD-L1 inhibition approaches are slated to be the backbone of cancer immunotherapy in the future. Drug development will focus on building on combinations with PD-1/PD-L1 to expand efficacy beyond the PD-1/PD-L1 inhibitor responders. Phase 1/2 combination studies with PD-1 inhibitors and several other immuno-oncology approaches have demonstrated encouraging early results in several clinical trials and in pre-clinical tumor models.

A notable pre-clinical example that suggests mechanistic synergy with PD-1 inhibition in combination with phosphatidylserine (PS) blockade (being developed by Peregrine Pharmaceuticals (PPHM)). PS is a differentiated immune checkpoint that tumors hijack to evade the immune response. The effect of PS inhibition complements inhibition of PD-1. Pre-clinical data suggests that combining PD-1 inhibition with inhibition of PS can result in meaningful synergies in the tumor microenvironment, re-polarizing the tumor microenvironment

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from an immunosuppressive state to an anti-tumor state.

The combination of PS blockade and PD-1 blockade shifts the immunosuppressive state to an anti-tumor state as observed by the changes in immune cell and cytokine profiles in the tumor microenvironment (Exhibit 4) or spleen (data not shown). This data was presented at ASCO 2015 in a mouse models of B16 melanoma, K1735 melanoma, and in EMT-6 breast tumor models. For example, in the tumor microenvironment (Exhibit 4) there is an increase in the number of CD8 T cells, dramatic increase in ratio of CD8/Tregs, increase in PD-1, Lag-3, IFN γ, TNF α and granzyme expression by CD8 T cells, an increase in the ratio of CD4/Tregs, increase in 4-1BB, IFN γ, TNF α, IL-2 expression/production by CD4 T cells. MDSCs are reduced (CD11b) and iNOS is increased on CD11b cells and PD-L1 expression on MDSCs is reduced. It must be noted that the combination therapy with PS inhibition induced changes that are over and above that achieved with PD-1 alone.

Exhibit 4: Combining phosphatidylserine (PS) and PD-1 blockade changes the immune profile in the tumor. The changes are shown as compared to PD-1 blockade alone. A dramatic change is observed from an immunosuppressive to an anti-tumor profile. If combination approaches that add on to PD-1 inhibition can catalyze such a dramatic pro-inflammatory/anti-tumor milieu, a robust tumor response may follow.

Reference: Peregrine Pharmaceuticals information, data presented at ASCO 2015

Chimeric Antigen Receptor (CAR) T cells: historical perspective, opportunity, future directions and concerns

In the simplest sense, the concept of CAR T cells is based on harvesting the cancer patients T cells, and then engineering the T cells ex-vivo. The T cells are engineered with a viral vector to express an artificial, or chimeric, receptor specific for a particular cancer-associated antigen (for example CD19 on B cells in the case of acute lymphocytic leukemia (ALL)). The engineered and primed T cells are then re-infused back into the patient. These CAR T cells are able to overcome the immune-suppression and inhibitory signals that tumors present and kill tumor cells like a natural CD8 T cell would exert its cytotoxic effects on tumor cells. It is notable that CAR T cell therapy is cell therapy, gene therapy, and immunotherapy all in one.

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Historical perspective

The concept of genetically engineered T cells is not entirely novel. Adoptive T cell transfer techniques with ex-vivo manipulation, expansion and then reinfusion were first tested decades ago in clinic to treat viral infections such as cytomegalovirus or Epstein Barr virus infections following hematopoietic stem cell transplantation (8). Steve Rosenberg's laboratory at the National Cancer Institute (NCI) pioneered adoptive T cell therapy. Rosenberg's laboratory showed that tumor infiltrating lymphocytes (TILs) can be isolated from excised tumor tissue, cultivated, activated and expanded ex vivo; and, on reinfusion, show promising efficacy in the clinic, particularly in the treatment of melanoma (1). The concept of CAR T cells developed as a means of introducing tumor specificity into adoptive T cell therapy. CAR T cell approaches are a modification of adoptive T cell transfer techniques where a modified T cell receptor (TCR) is engineered to usually express a single-chain variable fragment (scFV) of an antibody that recognizes the antigen of interest (e.g. CD19 on B cells). This approach of using an antigen binding region derived from an antibody was first demonstrated in 1993 (2). The CAR is anchored via a transmembrane domain to the T cell and one or more intracellular signaling domains that contribute effector, persistence or trafficking function. The first CAR T cell therapies started in 1996 and had little efficacy. Over time, with advances in molecular biology, T cell engineering and a better understanding of tumor immunology greater efficacy was achieved. For example, many CAR T cell approaches have engineered in them co-stimulator domains such as 4-1BB or CD28 that allow effector function signaling.

The most common mode of stable gene transfer to engineer CAR T cells are viral techniques (gamma retroviral or lentiviral vectors). Non-viral techniques include transposons and RNA electroporation. The advantage of using gamma retroviral or lentiviral vectors is low immunogenicity.

Opportunity

Clinical studies with CAR T cells have generated tremendous enthusiasm in the medical and investment community. The majority of the trials have been for B cell driven cancers, targeting CD-19. In particular, dramatic success has been observed in refractory B cell acute lymphoblastic leukemia (B-ALL). Response rates as much as 60-90% have been observed with sustained remissions as much as two years or more so far. These impressive response rates are limited to leukemias that are driven by a single antigen. In solid tumors, CAR T cell approaches have not shown the same success for good reason. Solid tumors are heterogeneous with diverse mutations that are not amenable to the first generation of CAR T cell approaches. Exhibit 5 lists the most important CD19 based CAR T cell studies that have been instrumental in driving the interest shown by investors and Big Pharma.

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Exhibit 5: Summary of important CD19 CAR T cell studies

Reference: Torka P & Griffiths EA. 2015

Future directions for CAR technologies

CAR T cells may be in their early stages of development, just like monoclonal antibodies were at one time, before optimization and improvement. Further optimization is required to make CAR T cells safer and limit toxicity. To address issues of safety, the next improvement in the engineering of CARs may be the introduction of a suicide gene so that CAR T cells can be depleted in cases of severe toxicity. CAR T cells with chimeric receptors that are activated on encountering inhibitory ligands such as PD-L1 may be able to overcome the immune-suppression in the tumor microenvironment. CAR T cells that are engineered with co-stimulators such as 4-1BB, or OX-40 or with cytokines such as IL-12 that trigger innate and adaptive immunity are in the future pipeline.

CAR T cells are not effective in solid tumors where there is significant phenotypic tumor heterogeneity and a high mutational burden compared to leukemias that are driven by a single antigen or single receptor such as CD19. However, CAR T cells may be engineered to release IL-12 that can enhance T cell activation as well as harnesses the innate immune response to destroy the tumor irrespective of antigen. That is, destroy tumors that

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are not recognized by the CAR T cells. Such engineered CAR T cells with a transgenic 'payload', are so-called TRUCK T cells or the ‘fourth-generation' CAR T cells (5). Potentially, bringing NK cells that are not antigen restricted in the tumor microenvironment could help CAR T cells directed at solid tumors.

Beyond T cells, CAR NK cells are also in development. NK or Natural Killer cells have attributes that make them ideal for cancer immunotherapy, however, NK cells are difficult to work with and make into a commercial drug opportunity. For example, past attempts to use autologous NK cells have not been successful as the activity is blocked by self- MHC. This can be overcome at least in part by using allogeneic donor NK cells. However, the process of isolation and expansion is labor-intensive and expensive as T cells must be removed by leukapherisis to avoid graft versus host disease (GVHD). In addition, the yield of NK cells is highly variable, the procedure is highly invasive and does not lend itself to repeat dosing.

NantKwest Therapeutics (discussed above) has developed a proprietary NK cell line (Neukoplast) engineered as a CAR NK cell. Development of such a cell line may solve some of the problems associated with NK cell therapy, as discussed above. Neukoplast has demonstrated safety and anti-cancer potency in Phase I trials including clinical responses in late-stage lung, kidney and melanoma cancers and long-term responses in relapsed lymphoma. The CAR NK cell program has not made it to clinic yet.

Concerns: safety issues, cost of CAR T cell therapy

Cytokine release syndrome (CRS) is the most common adverse event of CAR T cell therapy and it can be life threatening. To some extent, CRS is seen in most patients receiving anti-CD19 CAR T cells, with severe CRS reported in about 20 to 30% of patients. Symptoms of CRS are more acute when CD28 is engineered as part of the CAR T cell compared to 4-1BB. This is likely because CD28 induced co-stimulation results in more rapid T cell proliferation and activation. Neurotoxicity (delirium and seizure-like activity) is also observed in all CD19 CAR T cell trials in ALL. As expected, in the case of CD19 engineered CAR T cells there is risk of depletion of normal B-cells, B cell aplasia. This can result in increased risk of infection.

Costs associated with CAR T cell therapy are extremely high – maybe as high as $500K per patient given the genetic engineering and cell culture processes required. The process of autologous T cell harvesting, stable transfection of CAR and associated stimulatory sequences using retroviral or lentiviral vectors, sterile expansion of the transfected autologous CAR T cells, and then reinfusion back into the patient adds up in cost of manufacture and processing. Arguably, the rationale behind such an expensive therapeutic option maybe supported by durable and high response rates - as high as 90% in a subset of patients. However, for CAR T cell approaches to capture a broader patient population, such costs may be prohibitive for payors/HMOs and the healthcare system to sustain.

We note that immunotherapy in general is expensive – not just CAR T cells. While CAR T cells therapy may be as high as $500K per patients, immunotherapy with checkpoint inhibitors such as Opdivo and Keytruda are in

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the $150K range per patient. In particular, in the EU the cost is prohibitive and has to be justified for patients.

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Antibody engineering meets immunotherapy

The resurgence in immunotherapy was triggered by an antibody against CTLA-4 on T cells

Conventional antibody therapeutics, at least those that exert their effect via the Fc receptor (inducing ADCC etc.) and harness the immune response are in the immunotherapy category but are not normally viewed as so. Given that monoclonal antibodies have been around since the late 1980s when Janssen/J&J developed Orthoclone OKT3 – a murine monoclonal antibody against T cell CD3 receptor for transplant rejection. Note that the resurgence in immunotherapy was triggered with an antibody against CTLA-4 (Yervoy) on T cells that blocks its interaction with B7-1 and B7-2 on antigen presenting cells. Yervoy/anti-CTLA-4 blocks a negative regulator of the immune system and prevents inhibition of T cells, thus allowing an anti-tumor response.

Bispecific (and trispecific) antibodies reflect progress in antibody engineering; bispecific antibodies can circumvent cancer escape mechanisms

Antibody constructs with dual specificity were first described as anti-cancer therapeutics over 25 years ago. However, it was only recently that a subclass of bispecific antibodies - bispecific single-chain antibodies proved to be efficacious. The FDA approved Amgen's (AMGN) Blincyto (blinatumomab), a CD19- and CD3-targeting bispecific antibody for acute B-cell lymphoblastic leukemia. Micromet (acquired by Amgen) was the pioneer in developing Blincyto and bispecific antibodies, termed BiTE (bispecific T cell engager). Blincyto marks the first bispecific antibody approved by the FDA. Notably, a bispecific antibody was approved by the EU regulators in 2009 – catumaxomab that binds EpCAM (epithelial cell adhesion molecule) on tumor cells and CD3 on T cells. Catumaxomab has one anti-EpCAM and one anti-CD3 heavy and light chain. Bispecific antibody technology has evolved and improved since the approval of catumaxomab in 2009.

Bispecific antibodies address one of the major concerns in tumor immunotherapy i.e., circumventing immune-suppression or cancer escape mechanisms. For example, Blincyto by engaging CD19 on B-cells (tumor cells in B-cell ALL) and CD3 on T cells eliminates the need for antigen processing and presentation by functionally replacing the HLA/peptide/T cell receptor complex (6). Binding of Blincyto to CTLs results in activation and lysis of target CD19 expressing tumor cell. A single activated CD8 cytotoxic T cell (CTL) has the capacity to lyse several target tumor cells, expanding the antitumor effector response.

The concept behind recruiting CTLs in the proximity of the tumor using bispecific antibodies can be applied to the recruitment NK cells and therefor the innate immune response. Affimed (AFMD) is developing bispecifics that bind to CD16A on NK cells and a tumor antigen. Notable about Affimed's approach is its next generation bispecific antibody that are tandem diabodies (TandAbs). TandAbs are tetravalent bispecific molecules

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comprised of antibody variable domains with two binding sites for each antigen. This strategy has several advantages over first generation or conventional bispecific antibodies improving effector function - dual binding that can increase efficacy and improve the therapeutic window over current approaches. TandAbs do not carry Fc domains, are smaller than whole IgGs or IgG-derived bispecific antibodies, but larger than BiTEs. Therefore, they have a shorter serum half-life than IgGs but remain longer in the circulation compared with BiTEs (because they exceed the glomerular filtration cut-off size) (7).

Bispecific antibodies are also being developed in combination with checkpoint inhibitors and early signs are that there is good synergy in combination. Beyond bispecific antibodies, trispecific antibodies and engineered camelid antibodies (composed of two identical heavy chains) are in development - to be discussed in a future note.

Next-generation sequencing, single cell analysis, bioinformatics propels cancer immunotherapy drug development

Needless to say, the innovation and advances in research and development tools has propelled drug development in not just immunotherapy, but across all drug development. Technological advances in next-generation sequencing (NGS) and single cell analysis can personalize cancer immunotherapy. Furthermore, laboratory automation such as the development of devices for scanning whole-slide bioimages from tissue sections and image analysis software for quantitation of tumor-infiltrating lymphocytes (TILs) allow, for the first time, the development of personalized cancer immunotherapies that target patient specific mutations. Notably, no bioinformatics solution that supports the integration of these distinct datasets and research and development tools is available to date (4).

Challenges and questions ahead

While progress in cancer immunotherapy drug development has been dramatic, there remain many challenges to maximize the full potential of immunotherapy to further improve the rate of tumor responses and increase patient survival. We list a select number of the challenges:

Response rates with checkpoint inhibitors are still low since only 20-40% of patients respond

Can an early measure of a robust antigen specific T cell response be a reliable surrogate for clinical efficacy and increased survival?

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Are there well defined mechanism of action that mitigate risk such as predictive biomarkers?

Is it mandatory/preferable to activate an innate immune response (in addition to adaptive) to improve long term durable responses?

What antigens are good/safe targets?

Endpoints – chemotherapy or molecular targeted approaches not apt for immunotherapy endpoints

Big Pharma and cell based immunotherapy such as CAR T cells – can it fit with Big Pharma's model?

Cost of therapy – can our healthcare system sustain CAR T cell based potential pricing?

Combining immunotherapy and other modalities with immunotherapy – many approaches in development, which ones will be the winners?

Will single cell analysis and next generation sequencing help address the mutational burden and heterogeneity in tumors from patient to patient or from time to time in the same patient?

Will intense monitoring post primary treatment be helpful to prevent/pick refractory disease in patients - for example, measuring circulating tumor cells (CTCs) is already in practice today to evaluate tumor re-occurrence?

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References

1. Rosenberg, S. A., Packard, B. S., Aebersold, P. M., Solomon, D., Topalian, S. L., Toy, S. T., Simon, P., Lotze, M. T., Yang, J. C., Seipp, C. A. et al. (1988). Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N. Engl. J. Med. 319, 1676-1680.

2. Eshhar, Z., Waks, T., Gross, G. and Schindler, D. G. (1993). Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the γ or ζ subunits of the immunoglobulin and T cell receptors. Proc. Natl. Acad. Sci. USA 90, 720-724.

3. Torka P & Griffiths EA; Engineered T Cells for Leukemia: A Review of Current Approaches and Applications. http://www.targetedonc.com/publications/targeted-therapies-cancer/2015/june-2015/engineered-t-cells-for-leukemia-a-review-of-current-approaches-and-applications

4. Dander et al; Personalized Oncology Suite: integrating next-generation sequencing data and whole-slide bioimages. BMC Bioinformatics 2014, 15:306

5. Chmielewski M & Abken H; TRUCKs: the fourth generation of CARs. Expert Opin. Biol. Ther. (2015) 15(8)

6. Baeuerle PA et al; BiTE: Teaching antibodies to engage T-cells for cancer therapy; Current opinion in molecular therapeutics 11:1 2009 Feb pg 22-30

7. Roland E. Kontermann and Ulrich Brinkmann. Drug Discovery Today. Volume 20, Number 7 July 2015

8. Sharpe, M., and Mount, N. (2015). Genetically modified T cells in cancer therapy: opportunities and challenges. Disease Models & Mechanisms. 8, 337-350.

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NFCM RATING DEFINITIONS % OF STOCKS COVERED % OF IB CLIENTS

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HOLD: potential return is -15% to 15% of the current price 29% 3%

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