2015CAR-T峰会英文报道（英文.下）

林辉

Panel Discussion5 W2 u" C. n. I6 Z' E! b& h& }6 N

) a2 L, P; O. G6 R! S. \, HCutting edge efficacy data from improved CAR: What lessons have been learned so far to future proof clinically successful CAR-T cell therapies?3 s& O8 x& i  w& [6 X; }- Y

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The need to develop animal models for solid cancers- _0 W5 L7 ], J
        The panel first discussed the use of preclinical models for studying CAR-T efficacy against solid tumors. BS suggested the use of syngeneic mouse models to try replicate efficacy of CAR-Ts seen in liquid tumors to solid tumors. Sheof course, warned that mouse models never reveal the most accurate representation of how such therapies would work in humans. HA attested to her views by reasoning out that the tumor biology and microenvironment in mice is very different from that in humans. SE was unconvinced about NSG mouse models that are currently being used by most investigators, due to the inherent limitations of the model. He pointed out that there have been only a handful of publications using syngeneic mouse models. MK was skeptical about the mechanisms of CAR-resistance developed in murine models and if they were truly representative of what happens in humans.9 x+ [6 {8 t# |7 I' c: x( g' O  `

) x- H' ~& c! d7 c0 f6 zImmune response against CARs
4 A& G3 K3 t3 c1 }        A question rose about the risks involved in the induction of anti-CAR antibodies that could hamper CAR-effectiveness. To this, MK recalled that in a study done using a mesothelin-specific CAR at the University of Pennsylvania, the investigators saw some signs of antibodies against the CAR, but these did not have any adverse effects to the patients or to the effectiveness of the study. SE referred to the strategy his firm, Unum Therapeutics has developed. It uses antibody fragments, rather than single-chain variable fragments to reduce immunogenicity, they hope with enhanced success.  E4 j% N1 h+ V2 [$ X+ }
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Use of peripheral blood versus tissue-resident T cells& h; O3 r. [; G9 a2 ^
         Although all the panelists agreed that it was not yet possible to predict which of these would truly be “better”, SE talked about the differences in feasibility of acquiring the cells from these two different sources. He mentioned that the actual status of the patient at the time of apheresis or T cell acquisition would be an important factor to be considered.
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8 H* Z0 U3 X  j! vInteractive Discussion: CAR-T in the Round5 m9 w1 Z  U, i: P$ \. w+ K- v
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Bringing economically viable CAR-T therapies to market% f1 j/ X+ ]1 o+ |: v

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" W5 @, F; i- e# I' O" C. A. v“It is very difficult to put a price tag to the therapy”
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5 s4 t0 K! n' E& `: Q0 }4 t4 W; C( pThis round table session focused around the economics behind the CAR-T therapy and the value it brings to the patients undergoing this treatment. First off, SB was reluctant to talk about the expected price of therapy and clarified that pricing would not be the focus of this discussion. He laid out the common platform of how investigational therapies are brought out to the market. These, as he pointed out are manufacture and supply, regulatory dossier, value dossier and outcomes-based reimbursements. To assess how the outcomes-based reimbursements would be gauged, one of the members pointed out that the NCCA rolled out parameters to measure and realize the value of the therapy. SB grouped the patient into three segments, based on the outcomes – (1) the “hope” segment where the value has not yet been realized, (2) The “loss” segment, which comprises of patients who have seen some positive indications with the therapy but not yet completely recovered, and (3) the “optimum” segment where the patient sees the highest value of the therapy.- @' D, ^+ H5 G: D: |: _
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However, it would be very difficult for the payer to allocate patients into these groups solely based on medical indications/outcomes. This in turn makes it very difficult to put a price tag to the therapy.
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6 h0 B: P+ a5 [4 a( x- h' e! ROther questions raised during the discussion and which could not be answered to any satisfactory consensus amongst the crowd, included:$ G3 V, Y: F  B  z$ ^% @; T; }
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1. How may doses per patient?
/ }# M5 G. ~9 m$ g6 ]. i2. What would be the cost per dose or per regimen?: n6 I2 ?6 l& Y$ }0 f( ?2 R
3. When would the payments be made – before or after the therapy/outcomes?
( f) C" M  Q6 O' c& i& `9 e4.Does the hospital determine the cost?
/ `9 R* @6 N3 t6 U5 j! x/ A5.What about the follow-up costs?
# H. u; v/ {8 S9 k; Y6. Is affordability going to be more important than cost-effectiveness?
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“CAR-T technology is on the brink of becoming the new standard of care to treat cancer”
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With all these questions yet to be addressed, SB concluded that the CAR-T community has truly generated a disruptive strategy in the fight against cancer. He made an analogy to Rolls Royce, the car company that makes aircraft engines and Nespresso, a luxury café whose major sales are now from home coffee-brewing machines. He left the crowd to ponder over how both these firms have come out to be the most widely acknowledged brands in their respective arenas, having disrupted competition’s business – and how the CAR-T technology is on the brink of becoming the new standard of care to treat cancer.4 i9 z  Q% \& w* d0 O. |, B0 n
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“The speakers were truly all great. The meeting was a great update on the state of CAR T cell field from all the major players.”——Neil Michaud, Associate Director R&D Qualitative Analytics, Takeda
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Panel Discussion：How to Drive Down your Direct Cost of Goods and Foster Innovation to Execute a Commercially Viable CAR-T Therapy?+ X& a( c5 G4 t) t& l- @

* V) u) C( w. W5 A  A# U2020 From the Rear View Mirror' ~7 U' s8 c1 M* p8 H5 G+ B
      UA began the panel by setting that stage and painting a picture 5 years in the future. He transported us to 2020 and asked us to imagine adoptive cell immunotherapies had become a reality; they were accessible to patients around the world affordably. They were in the form of CARs and possibly other therapies treating hematological malignancies. There had also been significant progress in solid tumors.
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- |  E. A' w1 d5 @8 Z       He then asked the panel to reflect back from 2020 and think about how hindsight would change what they wish they had focused on in 2015?
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       PH highlighted that most of senior management tend to think in terms of margins. For example, what do we need to do to create a commercially viable margin protected product? He posed this interesting question base on the paradigm that cell and gene therapy is currently facing. There was a rapid transition from academia to industry however; they weren’t able to evaluate those processes that are used in a clinical setting vs. move to a process that is more specific to scaling up, he then went on to add the topic of value to the discussion.
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3 K/ L9 O' P- j4 N- ]$ @The Value Proposition. S5 l) p- ], r9 z3 E4 r
       AH talked about GSK factoring two important aspects into the value proposition conversation; one being modularity - different components of technology that have to come together in the right way to work together efficiently and effectively and the second being supply chain optimization. AH continues by highlighting the myriad challenges required to overcome both these things but finishes by stating at least directionally those two things, modularity and supply chain optimization will drive success.
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Labor As A Cost of Manufacturing
  Q9 S: `: j: @0 a      TB brought in an additional paradigm to consider labor as a major part of the costs of manufacturing, particularly when thinking of working in a clean room to the tune of thousands of patients, it becomes quite a challenge that perhaps automation of all or some of the process will eventually help to overcome. As a final point he also mentioned quality control as an expensive process, each of the individual assays themselves are processes of their own and can also be quite labor intensive, particularly potency assays.
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5 p0 q; }* H% I9 q5 ?2 l4 n        The panel went on to discuss the above challenges more extensively and highlighted the challenge of globalizing this type of therapy and integrating a supply chain into your development strategy.
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       UA closes by highlighting the varying efforts happening in the space throughout all the aspects of value chain, be that the starting material, thinking about cost of goods in the raw material setting, thinking about the time and place when it comes to indirect cost of goods as well.3 n, R3 e9 Q' p/ O5 w
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       Finally, he mentions that there is clearly a vision forming that CAR-T therapies could be scalable, adaptable, profitable systems, but this will necessitate courage and further investment over the next few years.
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4 \, U: \/ ]- G' C: Y2 ?Conclusion5 ]0 j  |& v9 O+ A( `! g
       The final presentation at the CAR-T summit didn’t leave a dry eye in the room. We heard from Tom Whitehead, the father of Emily Whitehead (the first patient to receive CAR-T therapy) and co-founder of the Emily Whitehead Foundation. Tom gave a very poignant and heartfelt presentation, sharing his and his families journey from diagnosis to receiving CAR-T therapy, the side effects that followed and seeing Emily come through all this and in remission three and a half years later. This presentation rounded off nicely why everyone in this room was doing what they were doing, putting into perspective what success in this field could mean for thousands of patients. Thus concluding two days full of discussions on the variety of ways to streamline CAR-T discovery, design and development and optimize on the future manufacturing, commercialization and global distribution strategies. There is still a long way to go and this meeting highlighted the many possibilities moving forward despite this, let us not forget how far the industry has already come.; k2 _# i, E4 F. F9 Y. [