2015CAR-T峰会报道（英文.上）

林辉

来源：CAR-T Summit 2015
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A Thank You From the CAR-T Summit Team) P1 j& L8 O# c4 G

+ F; p+ d; y/ |2 G5 RDear Attendee,
# o9 j( ^: r) {9 `: CFollowing the hugely successful CAR-T Summit in Boston, the team here at Hanson Wade and I would like to say a big thank to all those who participated in the event.
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Putting together these meetings is never possible without the support of our partners and I’d like to take the time to thank them for their continued support as we grow the meeting and look to 2016.
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The speakers whose research stimulated two days of conversation, interaction and solutions are integral to this meeting and I would like to thank each one of you for your huge contribution to the meeting. Your time and efforts were well received and we have been getting incredibly positive feedback.
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A personal thank you to Dr. Zelig Eshhar, the father of CAR-Ts, for taking the time to chair the 2015 meeting and share with us all his years of expertise. Also a special thank you to Tom Whitehead for sharing his family’s personal journey, from learning about Emily’s cancer to her 3 and a half years cancer free. The story was both poignant and inspiring.. t) ~0 ?* Z7 c/ W/ @$ k
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With many challenges on the horizon and still more questions than answers, the industry must come together and collaborate to succeed and with that we hope to see you all in 2016 to hear news on clinical updates, explore how to improve efficacy and potency of CAR-Ts, overcome the manufacturing and commercialization hurdles and bring these unique life changing therapies to market.
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Introduction
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The CAR-T summit held in Cambridge, Massachusetts on November 12-13, 2015 is the first of its kind, focusing solely on the application of Chimeric Antigen Receptors (CARs) in the therapeutic space. It assembled leaders from the pharmaceutical industry, academic institutions, service providers as well as non-profit organizations who have shared interests in bringing this promising therapy to the forefront of the battle against cancer. With an exceptional lineup of speakers and panelists over two days, we extensively discussed the status of the biology and economics behind CAR-Therapy, current issues plaguing this space as well as strategies for its future development. Below are some exclusive snippets from my two days. Omkar Kawalekar, Graduate Student at University of Pennsylvania./ B: r' m$ }5 B7 ?0 }4 j

8 f( }9 W( B0 m( Z, n# U- YKeynote Interviews3 D, r, C: e9 X# `  H2 W: m
How can the CAR-T community avoid another “Biologics Bubble” & deliver on the early clinical promise?
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0 Q9 B, L8 H; @2 X2 s+ MWhat are the challenges and risks in the commercialization of the CAR-T business?
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“Cost of goods sold aspect of disseminating this technology could be the bottle-neck”
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This “tight squeeze” of four prominent leaders in the CAR-T space primarily discussed the translational prospects of the clinical success seen with this therapy so far. MR was of the opinion that the most important challenge was to continue to demonstrate the safety and clinical efficacy, while the risks involved controlling the cytokine syndrome, toxicity and how to mitigate and treat side-effects. BL mentioned that funding was a major risk until now, but the field should continue to remain on the “plateau of enlightenment” and not go downhill. However, he pointed out the regulatory approvals pose a looming challenge. Additionally, he believes that the processmoving ahead has to become more automated to accommodate the multifold increase in patient number as this therapy scales up, adding that the logistics of sourcing a product derived of patient cells and infusing these back into said patients was challenging too in terms of infrastructure, suppliers and labor. SW agreed with the issues on logistics. He gave an example of how Novartis acquired a manufacturing facility from Dendreon to centralize the ex vivo manipulation process of CAR-Ts. His goal is to disseminate the manufacturing knowhow and process to remote centers. BL believes that this technology is still a long way from being made available at community centers as the quality-control and delivery processes are complex. Both him and MR agreed that comparability between remote sites and major centers would be a big challenge. CH believes that the COGS (Cost Of Goods Sold) aspect of disseminating this technology could be the bottle-neck and thus he summarized that one cannot predict how long it would take for the transfer.
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Durability and side-effects of CAR-Therapy
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“A “living drug” that was persistent and durable”
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9 P) H) a" Q8 j# N: MFrom BL’s experience, Cytokine Release Syndrome (CRS) seemed to be the major side effect and its severity increased in patients with high disease burden. One strategy in such patients was to space out the infusion of CAR-T cells. In terms of durability of response, BL pointed out that analysis of patient cells and tumors was being conducted routinely using state-of-the-art assays including PCR, flow cytometry and micro-arrays these assays can be used to predict response to therapy on a patient by patient basis. As a reference, he talked about a 15-year old HIV CAR-T study performed with MR at CellGenesys. In this trial, CAR-Ts infused in HIV patients brought about a modest decrease in viral load by 0.3 logs, but the important take-home was that CAR-Ts could be detected in patients even up to 10 years post infusion. He called these cells a “living drug” that was persistent and durable. His current trials with leukemic patients have detectable CAR-T cells even 5 years post infusion. CH mentioned that durability can be enhanced by multiple injections and MR talked about certain intrinsic factors, such as CAR design and manufacturing process that could increase durability; and extrinsic factors, including tumor mass, types and duration of treatment the patient has undergone prior to the CAR-T therapy conditioning regimen. She suggested that these should be carefully studied to optimize durability of CAR-T therapy.0 W/ F3 G8 b/ Q; v( S

( u& ?# c0 ~+ X) k  n9 zHow to deal with adverse events& c" s' {4 X* n# Q: V
SW mentioned that there is a wealth of knowledge from the trials done so far that paves opportunities to learn and improve the therapy further by mitigating adverse events. BL on the other hand said that he has never seen any genotoxicity in the 100+ patients that his group has treated. MR shrewdly pointed out the adverse events associated with CAR-Therapies have been discussed out of context. She reminded everyone that the patients on CAR-Trials are highly refractory with only a survival rate of 4-8 months. CAR-T therapies have improved these survival rates,albeit to varying durations. Kite Pharma’s KTC19 trials have reported that patients’ B cells and immunoglobulin revert back to normal levels after reduction in tumor burden caused by CAR-T infusions.
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Strategies to reduce cost of the technology- |' j) B/ v" k, p) ?6 ~
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“One should pay close attention to the complexity drivers in the manufacturing process”" u" B: ]1 q$ @' J# [5 Q" A
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SW claimed that this was an obvious challenge. He stressed on how one should pay close attention to the complexity drivers in the manufacturing process. These include, but are not restricted to: regional regulatory environment, raw materials, logistical supply chain as well as the engineering approaches utilized.
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  @/ M! ^4 ?! S; l  X3 Q( ^2 b# h) DUse of autologous versus allogeneic T cells as a starting material* @! A& s5 U/ i+ F

: b! y; G5 l( B4 ]. z  b“Any patient in any part of the world could receive this as an “off-the-shelf” therapy”: `9 h3 V9 E) t+ Y, o$ @" J
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CH considers the autologous approach more effective, however, the future goal should focus on adopting the allogeneic model so that “any” patient in any part of the world could receive this as an “off-the-shelf” therapy. BL believes that allogeneic cells could be used for short-term purposes as a bridge to other therapies. He is currently working on an animal model at the University of Pennsylvania to investigate this idea further. MR seemed wary about this approach. She pointed out that graft versus host disease is a major issue, and genetic manipulation of allogeneic cells has not undergone long-term survival and safety testing to make it a reliable source of CAR-Ts for infusions.6 j9 G+ F% j: r) S5 ^
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B cell aplasia  r! j0 Z0 l& X; ~1 s( _* k: t
Finally, as the session neared its close, a question raised by a member of the audience was regarding B cell aplasia and the cost associated with the intravenous replenishment of immunoglobulin (iv-Ig) post CD19 CAR-T therapy. BL mentioned that aplasia was related to the persistence of CAR-modified T cells grafted into the patient as well as the characteristics of the patient cells. Novel strategies, such as On/Off CARs and conditional CARs could help mitigate the need for iv-Ig issues. MR referred to the CAR constructs that her group at Kite Pharma has used which persist in patients for shorter time periods. Their studies suggest that patients with such CAR-T cells can come off iv-Ig sooner.
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% n9 X& X1 A3 j3 ]3 K) i, q“It's rare to attend a conference and find every talk of interest. The inaugural CAR-T Summit 2015 assembled experts and front line companies to create an engaging, informative conference with just the right amount of networking opportunities.”——Jeff Till, Director, External Innovation, EMD Serono